Progressive Decline in Hippocampal CA1 Volume in Individuals at Ultra-High-Risk for Psychosis Who Do Not Remit: Findings from the Longitudinal Youth at Risk Study.
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ABSTRACT:
SUBMITTER: Ho NF
PROVIDER: S-EPMC5437892 | biostudies-other | 2017 May
REPOSITORIES: biostudies-other
Publications
Progressive Decline in Hippocampal CA1 Volume in Individuals at Ultra-High-Risk for Psychosis Who Do Not Remit: Findings from the Longitudinal Youth at Risk Study.
Ho New Fei NF Holt Daphne J DJ Cheung Mike M Iglesias Juan Eugenio JE Goh Alex A Wang Mingyuan M Lim Joseph Kw JK de Souza Joshua J Poh Joann S JS See Yuen Mei YM Adcock Alison R AR Wood Stephen J SJ Chee Michael Wl MW Lee Jimmy J Zhou Juan J
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20170112 6
Most individuals identified as ultra-high-risk (UHR) for psychosis do not develop frank psychosis. They continue to exhibit subthreshold symptoms, or go on to fully remit. Prior work has shown that the volume of CA1, a subfield of the hippocampus, is selectively reduced in the early stages of schizophrenia. Here we aimed to determine whether patterns of volume change of CA1 are different in UHR individuals who do or do not achieve symptomatic remission. Structural MRI scans were acquired at base ...[more]
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Project description:Although schizophrenia is characterized by gray matter (GM) abnormalities, particularly in the prefrontal and temporal cortices, it is unclear whether cerebral cortical GM is abnormal in individuals at ultra-high-risk (UHR) for psychosis. We addressed this issue by studying cortical thickness in this group with magnetic resonance imaging (MRI). We measured cortical thickness of 29 individuals with no family history of psychosis at UHR, 31 patients with schizophrenia, and 29 healthy matched control subjects using automated surface-based analysis of structural MRI data. Hemispheric mean and regional cortical thickness were significantly different according to the stage of the disease. Significant cortical differences across these 3 groups were found in the distributed area of cerebral cortices. UHR group showed significant cortical thinning in the prefrontal cortex, anterior cingulate cortex, inferior parietal cortex, parahippocampal cortex, and superior temporal gyrus compared with healthy control subjects. Significant cortical thinning in schizophrenia group relative to UHR group was found in all the regions described above in addition with posterior cingulate cortex, insular cortex, and precentral cortex. These changes were more pronounced in the schizophrenia group compared with the control subjects. These findings suggest that UHR is associated with cortical thinning in regions that correspond to the structural abnormalities found in schizophrenia. These structural abnormalities might reflect functional decline at the prodromal stage of schizophrenia, and there may be progressive thinning of GM cortex over time.
| S-EPMC3122277 | biostudies-other
Project description:The addition of off-the-shelf cognitive measures to established prodromal criteria has resulted in limited improvement in the prediction of conversion to psychosis. Tests that assess cognitive processes central to schizophrenia might better identify those at highest risk. The latent inhibition paradigm assesses a subject's tendency to ignore irrelevant stimuli, a process integral to healthy perceptual and cognitive function that has been hypothesized to be a key deficit underlying the development of schizophrenia. In this study, 142 young people at ultra high-risk for developing psychosis and 105 controls were tested on a within-subject latent inhibition paradigm. Additionally, we later inquired about the strategy that each subject employed to complete the test, and further investigated the relationship between reported strategy and the extent of latent inhibition exhibited. Unlike controls, ultra high-risk subjects did not demonstrate a significant latent inhibition effect. This difference between groups became greater when controlling for strategy. The lack of latent inhibition effect in our ultra high-risk sample suggests that individuals at ultra high-risk for psychosis are impaired in their allocation of attentional resources based on past predictive value of repeated stimuli. This fundamental deficit in the allocation of attention may contribute to the broader array of cognitive impairments and clinical symptoms displayed by individuals at ultra high-risk for psychosis.
| S-EPMC5514297 | biostudies-other
Project description:Treatment in the ultra-high risk stage for a psychotic episode is critical to the course of symptoms. Markers for the development of psychosis have been studied, to optimize the detection of people at risk of psychosis. One possible marker for the transition to psychosis is social cognition. To estimate effect sizes for social cognition based on a quantitative integration of the published evidence, we conducted a meta-analysis of social cognitive performance in people at ultra high risk (UHR).A literature search (1970-July 2015) was performed in PubMed, PsychINFO, Medline, Embase, and ISI Web of Science, using the search terms 'social cognition', 'theory of mind', 'emotion recognition', 'attributional style', 'social knowledge', 'social perception', 'empathy', 'at risk mental state', 'clinical high risk', 'psychosis prodrome', and 'ultra high risk'. The pooled effect size (Cohen's D) and the effect sizes for each domain of social cognition were calculated. A random effects model with 95% confidence intervals was used.Seventeen studies were included in the analysis. The overall significant effect was of medium magnitude (d = 0.52, 95% Cl = 0.38-0.65). No moderator effects were found for age, gender and sample size. Sub-analyses demonstrated that individuals in the UHR phase show significant moderate deficits in affect recognition and affect discrimination in faces as well as in voices and in verbal Theory of Mind (TOM). Due to an insufficient amount of studies, we did not calculate an effect size for attributional bias and social perception/ knowledge. A majority of studies did not find a correlation between social cognition deficits and transition to psychosis, which may suggest that social cognition in general is not a useful marker for the development of psychosis. However some studies suggest the possible predictive value of verbal TOM and the recognition of specific emotions in faces for the transition into psychosis. More research is needed on these subjects.The published literature indicates consistent general impairments in social cognition in people in the UHR phase, but only very specific impairments seem to predict transition to psychosis.
| S-EPMC4624797 | biostudies-literature
Project description:Most individuals at ultra-high risk (UHR) for psychosis do not transition to frank illness. Nevertheless, many have poor clinical outcomes and impaired psychosocial functioning. This study used voxel-based morphometry to investigate if baseline grey and white matter brain densities at identification as UHR were associated with functional outcome at medium- to long-term follow-up. Participants were help-seeking UHR individuals (n = 109, 54M:55F) who underwent magnetic resonance imaging at baseline; functional outcome was assessed an average of 9.2 years later. Primary analysis showed that lower baseline grey matter density, but not white matter density, in bilateral frontal and limbic areas, and left cerebellar declive were associated with poorer functional outcome (Social and Occupational Functioning Assessment Scale [SOFAS]). These findings were independent of transition to psychosis or persistence of the at-risk mental state. Similar regions were significantly associated with lower self-reported levels of social functioning and increased negative symptoms at follow-up. Exploratory analyses showed that lower baseline grey matter densities in middle and inferior frontal gyri were significantly associated with decline in Global Assessment of Functioning (GAF) score over follow-up. There was no association between baseline grey matter density and IQ or positive symptoms at follow-up. The current findings provide novel evidence that those with the poorest functional outcomes have the lowest grey matter densities at identification as UHR, regardless of transition status or persistence of the at-risk mental state. Replication and validation of these findings may allow for early identification of poor functional outcome and targeted interventions.
| S-EPMC5605267 | biostudies-literature
Project description:Background:The diagnostic and prognostic significance of the DSM-5-defined Attenuated Psychosis Syndrome (DSM-5-APS) in individuals undergoing an ultra high risk (UHR) clinical assessment for suspicion of psychosis risk is unknown. Methods:Prospective cohort study including all consecutive help-seeking individuals undergoing both a DSM-5-APS and a Comprehensive Assessment of At Risk Mental States (CAARMS 12/2006) assessment for psychosis risk at the Outreach and Support in South London (OASIS) UHR service (March 2013-April 2014). The diagnostic significance of DSM-5-APS was assessed with percent overall agreement, prevalence bias adjusted kappa, Bowker's test, Stuart-Maxwell test, residual analysis; the prognostic significance with Cox regression, Kaplan-Meier failure function, time-dependent area under the curve (AUC) and net benefits analysis. The impact of specific revisions of the DSM-5-APS was further tested. Result:In 203 help-seeking individuals undergoing UHR assessment, the agreement between the DSM-5-APS and the CAARMS 12/2006 was only moderate (kappa 0.59). Among 142 nonpsychotic cases, those meeting DSM-5-APS criteria had a 5-fold probability (HR = 5.379) of developing psychosis compared to those not meeting DSM-5-APS criteria, with a 21-month cumulative risk of psychosis of 28.17% vs 6.49%, respectively. The DSM-5-APS prognostic accuracy was acceptable (AUC 0.76 at 24 months) and similar to the CAARMS 12/2006. The DSM-5-APS designation may be clinically useful to guide the provision of indicated interventions within a 7%-35% (2-year) range of psychosis risk. The removal of the criterion E or C of the DSM-5-APS may improve its prognostic performance and transdiagnostic value. Conclusions:The DSM-5-APS designation may be clinically useful in individuals accessing clinical services for psychosis prevention.
| S-EPMC5814820 | biostudies-other
Project description:Recent microarray studies in the hippocampus of rodents or Alzheimerâs disease (AD) subjects have identified a substantial number of cellular pathways/processes correlated with aging and cognitive decline. However, the temporal relationships among these expression changes or with cognitive impairment have not been studied in depth. Here, using Affymetrix microarrays, immunohistochemistry and Morris water maze cognitive testing across 5 age groups of male F344 rats (n=9-15/group, one microarray per animal), we systematically analyzed the temporal sequence and cellular localization of aging changes in expression. These were correlated with performance scores on the hippocampus-dependent Morris Water Maze task. Significant microarray results were sorted in to Early, Intermediate, Midlife, and Late patterns of expression, and functionally categorized (Early- downregulated neural development, lipid synthesis and energy-utilization; upregulated ribosomal synthesis, growth, stress/inflammatory, lysosome and protein/lipid degradation. Intermediate- increased defense/inflammatory activation and decreased transporter activity; Midlife- downregulated energy-dependent signaling and neurite growth, upregulated astroglial activation, Ca2+-binding, cholesterol/lipid trafficking, myelinogenic processes and additional lysosome/inflammation; Late- further recruitment of genes in already-altered pathways). Immunohistochemistry revealed a primarily astrocytic localization of the processes upregulated in midlife, as well as increased density of myelin proteins. Evidence of cognitive impairment first appeared in the 12-month-old group (midlife) and was increased further in the 23-month-old group, exhibiting the highest correlations with some upregulated genes related to cholesterol transport (e.g., Apoe, Abca2), protein management and ion binding. Some upregulated genes for inflammation (Il6st) and myelinogenesis (Pmp22) also correlated with impairment. Together, the data are consistent with a novel sequential cascade model of brain aging in which metabolic alterations early in maturity are followed by inflammation and midlife activation of an astrocyte-centered cholesterol trafficking pathway that stimulates oligodendrocyte remyelination programs. Importantly, this cholesterol trafficking pathway also may compete for astroglial bioenergetic support of neurons, in turn, leading to downregulation of energy-dependent pathways needed to sustain cognitive functions. Experiment Overall Design: Fisher 344 rats aged 3 (n = 9), 6 (n = 9), 9 (n = 9), 12 (n = 9), or 25 (n = 15; but see below) months were behaviorally characterized on the Morris water maze. Briefly, animals were placed in a circular water bath chamber with a partially submerged platform. Three times per day for three days, animals were placed at randomized starting points with the goal of locating the hidden platform. Generally, animals became better at locating the platform, and by the third day of training, were reliably swimming directly to the platform despite randomized starting loci. On the fourth day, the platform was removed and the degree to which the animals focused their searches on the area that previously contained the platform was measured. On the last day of behavior, animals were given a cue trial in which the platform was raised above the water level so that the rats could see it. Measures taken from the behavior study included path length (how long did the animal swim prior to locating the platform/ platform area), latency to platform in seconds, and velocity (centimeters/ second; swim speed). Two aged animals (E2 and E12) were removed from the study for poor health, reducing the 23 month cohort (n = 13). Twelve to twenty four hours after the last behavioral session, animals were killed and their hippocampi removed. The right hippocampus went to immunohistochemistry for quantification and localization of selected protein products. The left hippocampus was dissected, the CA1 region removed and frozen in dry ice prior to microarray processing. mRNA was extracted from each animal's tissue by standard Affymetrix protocols (see Blalock et al., 2003) and hybridized to individual microarrays (RAE 230A; N = 49 arrays in total). Results were processed with the MAS5 algorithm and subjected to âall probe setâ scaling with a target intensity of 500. Probe sets were filtered for presence (> = 5 presence calls study wide) and gene symbol level annotation prior to statistical analysis. 1-ANOVA across age was used to identify aging-related probe sets/genes (p <= 0.05). Aging-related genes were subjected to post hoc template correlation to determine the pattern of age-related change, and further, within the 12 and 23 month old groups, Pearson's correlation with behavioral scores was used to identify genes whose expression levels correlated significantly (p <= 0.05) with behavior. Twelve and 23 month old groups were chosen for this correlation analysis as they showed the greatest variability among similarly aged animals, suggesting that these ages show important cognitive transition phases during aging-related cognitive decline. Functional grouping analysis was performed using the DAVID suite of on-line tools.
2009-01-25 | E-GEOD-9990 | biostudies-arrayexpress
Project description:IntroductionHippocampal abnormalities have been widely studied in schizophrenia spectrum populations including those at ultrahigh risk (UHR) for psychosis. There have been inconsistent findings concerning hippocampal morphology prior to and during the transition to psychosis, and little is known about how specific subregions are related to the symptom progression.MethodsA total of 80 participants (38 UHR and 42 healthy controls) underwent a 3T MRI scan, as well as structured clinical interviews. Shape analysis of hippocampi was conducted with FSL/FIRST vertex analysis to yield a localized measure of shape differences between groups. A subgroup of the sample (24 UHR and 24 controls) also returned for a 12-month clinical follow-up assessment.ResultsThe UHR group exhibited smaller hippocampal volumes bilaterally, and shape analysis revealed significant inversion in the left ventral posterior hippocampus in the UHR group. Greater inversion in this subregion was related to elevated symptomatology at baseline and increased positive symptoms, negative symptoms, and impaired tolerance to normal stress 12 months later. These results did not hold when left hippocampal volume was used as a predictor instead.DiscussionThis represents the first study to use vertex analysis in a UHR sample and results suggest that abnormalities in hippocampal shape appear to reflect underlying pathogenic processes driving the progression of illness. These findings suggest that examining shape and volume may provide an important new perspective for our conception of brain alterations in the UHR period.
| S-EPMC4681548 | biostudies-literature
Project description:BackgroundThe superior temporal gyrus (STG) is one of the key regions implicated in psychosis, given that abnormalities in this region are associated with an increased risk of conversion from an at-risk mental state to psychosis. However, inconsistent results regarding the functional connectivity strength of the STG have been reported, and the regional heterogeneous characteristics of the STG should be considered.MethodsTo investigate the distinctive functional connection of each subregion in the STG, we parcellated the STG of each hemisphere into three regions: the planum temporale, Heschl's gyrus, and planum polare. Resting-state functional magnetic resonance imaging was obtained from 22 first-episode psychosis (FEP) patients, 41 individuals at ultra-high-risk for psychosis (UHR), and 47 demographically matched healthy controls.ResultsSignificant group differences (in seed-based connectivity) were demonstrated in the left planum temporale and from both the right and left Heschl's gyrus seeds. From the left planum temporale seed, the FEP and UHR groups exhibited increased connectivity to the bilateral dorsolateral prefrontal cortex. In contrast, the FEP and UHR groups demonstrated decreased connectivity from the bilateral Heschl's gyrus seeds to the dorsal anterior cingulate cortex. The enhanced connectivity between the left planum temporale and right dorsolateral prefrontal cortex was positively correlated with positive symptom severity in individuals at UHR (r = .34, p = .03).ConclusionsThese findings corroborate the fronto-temporal connectivity disruption hypothesis in schizophrenia by providing evidence supporting the altered fronto-temporal intrinsic functional connection at earlier stages of psychosis. Our data indicate that subregion-specific aberrant fronto-temporal interactions exist in the STG at the early stage of psychosis, thus suggesting that these aberrancies are the neural underpinning of proneness to psychosis.
| S-EPMC4534425 | biostudies-literature
Project description:Prospective studies have suggested genetic variation in the neuregulin 1 (NRG1) and D-amino-acid oxidase activator (DAOA) genes may assist in differentiating high-risk individuals who will or will not transition to psychosis. In a prospective cohort (follow-up=2.4-14.9 years) of 225 individuals at ultra-high risk (UHR) for psychosis, we assessed haplotype-tagging single-nucleotide polymorphisms (htSNPs) spanning NRG1 and DAOA for their association with transition to psychosis, using Cox regression analysis. Two NRG1 htSNPs (rs12155594 and rs4281084) predicted transition to psychosis. Carriers of the rs12155594 T/T or T/C genotype had a 2.34 (95% confidence interval (CI)=1.37-4.00) times greater risk of transition compared with C/C carriers. For every rs4281084 A-allele the risk of transition increased by 1.55 (95% CI=1.05-2.27). For every additional rs4281084-A and/or rs12155594-T allele carried the risk increased ?1.5-fold, with 71.4% of those carrying a combination of ?3 of these alleles transitioning to psychosis. None of the assessed DAOA htSNPs were associated with transition. Our findings suggest NRG1 genetic variation may improve our ability to identify UHR individuals at risk for transition to psychosis.
| S-EPMC3641410 | biostudies-literature
Project description:In a recent machine learning study classifying "brain age" based on cross-sectional neuroanatomical data, clinical high-risk (CHR) individuals were observed to show deviation from the normal neuromaturational pattern, which in turn was predictive of greater risk of conversion to psychosis and a pattern of stably poor functional outcome. These effects were unique to cases who were between 12 and 17 years of age when their prodromal and psychotic symptoms began, suggesting that neuroanatomical deviance observable at the point of ascertainment of a CHR syndrome marks risk for an early onset form of psychosis. In the present study, we sought to clarify the pattern of neuroanatomical deviance linked to this "early onset" form of psychosis and whether this deviance is associated with poorer premorbid functioning. T1 MRI scans from 378 CHR individuals and 190 healthy controls (HC) from the North American Prodrome Longitudinal Study (NAPLS2) were analyzed. Widespread smaller cortical volume was observed among CHR individuals compared with HC at baseline evaluation, particularly among the younger group (i.e., those who were 12 to 17 years of age). Moreover, the younger CHR individuals who converted or presented worsened clinical symptoms at follow-up (within 2 years) exhibited smaller surface area in rostral anterior cingulate, lateral and medial prefrontal regions, and parahippocampal gyrus relative to the younger CHR individuals who remitted or presented a stable pattern of prodromal symptoms at follow-up. In turn, poorer premorbid functioning in childhood was associated with smaller surface area in medial orbitofrontal, lateral frontal, rostral anterior cingulate, precuneus, and temporal regions. Together with our prior report, these results are consistent with the view that neuroanatomical deviance manifesting in early adolescence marks vulnerability to a form of psychosis presenting with poor premorbid adjustment, an earlier age of onset (generally prior to the age of 18 years), and poor long-term outcome.
| S-EPMC6541907 | biostudies-literature