Cognitive Decline In Schizophrenia Research Articles

Association between reduced plasma BDNF concentration and MMSE scores in both chronic schizophrenia and mild cognitive impairment

Reduced brain derived neurotrophic factor (BDNF) concentration is reported to be associated with a cognitive decline in schizophrenia, depending on the stage of the disease. Aim of the study was to examine the possible association between plasma BDNF and cognitive decline in chronic stable schizophrenia and mild cognitive impairment (MCI). The study included 123 inpatients of both sexes with schizophrenia, 123 patients with MCI and 208 healthy control subjects. Cognitive abilities were assessed using mini mental state examination (MMSE), Clock Drawing test (CDT) and cognitive subscale of the Positive and Negative Syndrome Scale (PANSS). Plasma BDNF concentration was determined using ELISA. BDNF concentration was lower in patients with schizophrenia and MCI compared to age-matched healthy controls and was similar in carriers of different BDNF Val/66Met genotypes. The MMSE and CDT scores were lower in patients with schizophrenia compared to healthy controls and subjects with MCI. Reduced plasma BDNF was significantly associated with lower MMSE scores in all subjects. BDNF concentration in patients with schizophrenia was not affected by clinical and demographic factors. BDNF Val66Met polymorphism was not associated with the MMSE scores in all participants. Further studies should include longitudinal follow-up and other cognitive scales to confirm these results and offer cognition-improving strategies to prevent cognitive decline in chronic schizophrenia.

Baseline global brain structural and functional alterations at the time of symptom onset can predict subsequent cognitive deterioration in drug-naïve first-episode schizophrenia patients: Evidence from a follow-up study.

Alterations in the global brain gray matter volume (gGMV) and global functional connectivity density (gFCD) play a pivotal role in the cognitive impairment and further deterioration in schizophrenia. This study aimed to assess the correlation between alterations in the gGMV and gFCD at baseline (ΔgGMV and ΔgFCD), and the subsequent alterations of cognitive function in schizophrenia patients after 2-year antipsychotic treatment. Global-brain magnetic resonance imaging scans were acquired from 877 drug-naïve, first-episode schizophrenia patients at baseline and after two years of antipsychotic treatment with adequate dosage and duration, and 200 healthy controls. According to ΔgGMV at baseline, schizophrenia patients were divided into mild, moderate, and severe alteration groups. The MATRICS consensus cognitive battery and Global Deficit Score (GDS) were used to assess cognitive impairment. We found that ΔgGMV and ΔgFCD at baseline were significantly correlated with the severity of the cognitive deterioration (ΔGDS). The correlation coefficient indicated a significant positive correlation between baseline ΔgFCD and subsequent cognitive deterioration, with a relatively stronger relation in the mild alteration group (r = 0.31). In addition, there was a significant positive correlation between baseline ΔgGMV and subsequent cognitive deterioration, with a stronger relation in the moderate and severe alteration groups (r = 0.303; r = 0.302, respectively). Our results showed that ΔgGMV and ΔgFCD are correlated with the severity of cognitive deterioration after completion of a 2-year antipsychotic treatment in schizophrenia patients. These findings suggest that baseline alterations in gGMV and gFCD hold potential for predicting subsequent cognitive decline in schizophrenia.

Impaired inhibition of return during free-viewing behaviour in patients with schizophrenia

Schizophrenia affects various aspects of cognitive and behavioural functioning. Eye movement abnormalities are commonly observed in patients with schizophrenia (SZs). Here we examined whether such abnormalities reflect an anomaly in inhibition of return (IOR), the mechanism that inhibits orienting to previously fixated or attended locations. We analyzed spatiotemporal patterns of eye movement during free-viewing of visual images including natural scenes, geometrical patterns, and pseudorandom noise in SZs and healthy control participants (HCs). SZs made saccades to previously fixated locations more frequently than HCs. The time lapse from the preceding saccade was longer for return saccades than for forward saccades in both SZs and HCs, but the difference was smaller in SZs. SZs explored a smaller area than HCs. Generalized linear mixed-effect model analysis indicated that the frequent return saccades served to confine SZs’ visual exploration to localized regions. The higher probability of return saccades in SZs was related to cognitive decline after disease onset but not to the dose of prescribed antipsychotics. We conclude that SZs exhibited attenuated IOR under free-viewing conditions, which led to restricted scene scanning. IOR attenuation will be a useful clue for detecting impairment in attention/orienting control and accompanying cognitive decline in schizophrenia.

Structurally Diverse Positive Allosteric Modulators of the D1 Dopamine Receptor Potentiate G‐Protein and β‐Arrestin‐Mediated Signaling

The D1 dopamine receptor (D1R) is linked to a variety of neuropsychiatric disorders and represents an attractive drug target for the enhancement of cognition. Agents that enhance D1R signaling in the prefrontal cortex may be useful in the treatment of cognitive decline in schizophrenia, Alzheimer's disease and other disorders. Unfortunately, orthosteric D1R agonists have proved problematic as they frequently induce hypotension and exhibit a narrow therapeutic window. An alternative approach is to potentiate D1R activity using allosteric modulation. Hypothetically, a positive allosteric modulator of the D1R may exhibit highly selective actions and exhibit a larger therapeutic window. In order to identify allosteric ligands of the D1R, we implemented a high throughput screen of the NIH Molecular Libraries Program 400,000+ small molecule library. A D1R‐G15 calcium mobilization assay was used to identify library compounds that potentiated an EC20 concentration of dopamine. Initial hit compounds were characterized using endogenous G‐protein (cAMP stimulation) and ®‐arrestin (recruitment) signaling pathways, and parental cell lines were used as negative controls. A pool of compounds that exhibited positive allosteric modulation (PAM) of the D1R were identified and further counter‐screened against other dopamine receptor subtypes to establish subtype selectivity. Two structurally diverse compounds, MLS6585 and MLS1082, with PAM activity at the D1R were selected as lead compounds. These compounds potentiate both G‐protein and ®‐arrestin‐mediated D1R signaling, increasing the potency of dopamine by 5–10 fold for stimulating cAMP accumulation and 4–8 fold and for β‐arrestin recruitment. Both compounds also increased the maximum dopamine‐stimulated responses by 25–30%. Neither compound displayed any intrinsic agonist activity in either assay. Further, the two compounds displayed minimal to no ability to inhibit radioligand binding to the orthosteric‐binding site of the D1R. Both compounds potentiated the agonist activity of dopamine, as well as other full and partial agonists, in a dose‐dependent manner with EC50 values in the micromolar range. Importantly, they showed no ability to potentiate forskolin‐stimulated cAMP accumulation, or β‐arrestin recruitment by other receptor subtypes. MLS1082 and MLS6585 may serve as important scaffolds for the future development of optimized D1R PAMs for in vivo use and the discovery of therapeutic lead compounds.Support or Funding InformationNINDS Intramural Research Program

Altered neural signaling and immune pathways in peripheral blood mononuclear cells of schizophrenia patients with cognitive impairment: A transcriptome analysis

Cognitive deficits are a core feature of schizophrenia and contribute significantly to functional disability. We investigated the molecular pathways associated with schizophrenia (SZ; n=47) cases representing both ‘cognitive deficit’ (CD; n=22) and ‘cognitively spared’ (CS; n=25) subtypes of schizophrenia (based on latent class analysis of 9 cognitive performance indicators), compared with 49 healthy controls displaying ‘normal’ cognition. This was accomplished using gene-set analysis of transcriptome data derived from peripheral blood mononuclear cells (PBMCs). We detected 27 significantly altered pathways (19 pathways up-regulated and 8 down-regulated) in the combined SZ group and a further 6 pathways up-regulated in the CS group and 5 altered pathways (4 down-regulated and 1 up-regulated) in the CD group. The transcriptome profiling in SZ and cognitive subtypes were characterized by the up-regulated pathways involved in immune dysfunction (e.g., antigen presentation in SZ), energy metabolism (e.g., oxidative phosphorylation), and down-regulation of the pathways involved in neuronal signaling (e.g., WNT in SZ/CD and ERBB in SZ). When we looked for pathways that differentiated the two cognitive subtypes we found that the WNT signaling was significantly down-regulated (FDR<0.05) in the CD group in accordance with the combined SZ cohort, whereas it was unaffected in the CS group. This suggested suppression of WNT signaling was a defining feature of cognitive decline in schizophrenia. The WNT pathway plays a role in both the development/function of the central nervous system and peripheral tissues, therefore its alteration in PBMCs may be indicative of an important genomic axis relevant to cognition in the neuropathology of schizophrenia.

Poor premorbid school performance, but not severity of illness, predicts cognitive decline in schizophrenia in midlife

Neurocognitive dysfunction is common in schizophrenia but its course and determinants remain uncertain. Our aim was to analyse if premorbid school performance and the severity of illness and functioning predict change in cognition in schizophrenia in a general population sample.The sample included cases with schizophrenia spectrum disorder from the Northern Finland Birth Cohort 1966. Data on school marks at the age of 16years, educational level at the age of 34years, severity of symptoms and occupational functioning around first episode and after years of illness were gained from national registers, hospital notes and interviews. Change of verbal and visual learning and memory and executive functioning were examined between ages 34 and 43years. The number of cases varied in analyses from 29 to 41, depending on missing data in particular cognitive tests.Lower school marks at age 16 years and lower education at age 34 years predicted more decline of cognition. Measures of severity of illness or functioning were not associated statistically significantly with change of cognition.Premorbid school performance, but not later course of schizophrenia, related to change of cognition in midlife. Poor premorbid scholastic performance and post-onset cognitive decline may represent related processes as part of an endophenotype of schizophrenia.

Developmental Lag and Course of Cognitive Deficits From the Premorbid to Postonset Period in Schizophrenia

Developmental Lag and Course of Cognitive Deficits From the Premorbid to Postonset Period in Schizophrenia

EPA-0505 - NRG1 and DISC1 gene polymorphisms with respect to cognitive endophenotype in schizophrenia

Background Neuregulin-1 (NRG1) and DISC1 may be important factors in pathogenesis of schizophrenia due to their role in neurodevelopmental processes. NRG1 and DISC1 link directly into a common pathway mediated by Erb receptors and P13K/AKT1 signaling and have been implied to play role in cognitive impairments. Digit Symbol Coding Task (DSCT) from WAIS-R is a sensitive measure for cognitive decline in schizophrenia as well as it indexes poor prognosis and functional disability in schizophrenia. Purpose The study was carried out to investigate the association of a polymorphisms of the NRG1 gene (rs62510682) as well as of DISC1 gene (rs1538979) and schizophrenia with respect to performance on DSCT. Material and methods We included 103 patients diagnosed with schizophrenia according to ICD-10 criteria and 578 controls. In addition to unstructured interviews and review of medical records, the patients were evaluated for lifetime psychotic symptomatology using OPCRIT checklist. DCSTR was administered to 80 patients. Results The polymorphisms were in HWE for healthy controls and schizophrenia patients. In single marker analysis, we did not find an association for the SNPs tested. However; with respect to DCST we found that with respect to NRG1 gene T allel carriers performed worse than G allel carriers (p DISC1 gene patients with TC genotype performed worse than with CC genotype (p Conclusion Our data do not support the role of NRG1 or DISC gene polymorphisms in the predisposition to schizophrenia; however, they might be considered as risk factors for the cognitive decline in schizophrenia.

Genome-Wide Association Study of Cognitive Decline in Schizophrenia

Genome-Wide Association Study of Cognitive Decline in Schizophrenia

Mapping the pathophysiology of schizophrenia: interactions between multiple cellular pathways

Mapping the pathophysiology of schizophrenia: interactions between multiple cellular pathways

Dopamine D4 Receptor Activation Increases Hippocampal Gamma Oscillations by Enhancing Synchronization of Fast-Spiking Interneurons

BackgroundGamma oscillations are electric activity patterns of the mammalian brain hypothesized to serve attention, sensory perception, working memory and memory encoding. They are disrupted or altered in schizophrenic patients with associated cognitive deficits, which persist in spite of treatment with antipsychotics. Because cognitive symptoms are a core feature of schizophrenia it is relevant to explore signaling pathways that potentially regulate gamma oscillations. Dopamine has been reported to decrease gamma oscillation power via D1-like receptors. Based on the expression pattern of D4 receptors (D4R) in hippocampus, and pharmacological effects of D4R ligands in animals, we hypothesize that they are in a position to regulate gamma oscillations as well.Methodology/Principal FindingsTo address this hypothesis we use rat hippocampal slices and kainate-induced gamma oscillations. Local field potential recordings as well as intracellular recordings of pyramidal cells, fast-spiking and non-fast-spiking interneurons were carried out. We show that D4R activation with the selective ligand PD168077 increases gamma oscillation power, which can be blocked by the D4R-specific antagonist L745,870 as well as by the antipsychotic drug Clozapine. Pyramidal cells did not exhibit changes in excitatory or inhibitory synaptic current amplitudes, but inhibitory currents became more coherent with the oscillations after application of PD168077. Fast-spiking, but not non-fast spiking, interneurons, increase their action potential phase-coupling and coherence with regard to ongoing gamma oscillations in response to D4R activation. Among several possible mechanisms we found that the NMDA receptor antagonist AP5 also blocks the D4R mediated increase in gamma oscillation power.Conclusions/SignificanceWe conclude that D4R activation affects fast-spiking interneuron synchronization and thereby increases gamma power by an NMDA receptor-dependent mechanism. This suggests that converging deficits on fast-spiking interneurons may lead to decreased network function and thus aberrant gamma oscillations and cognitive decline in schizophrenia.

Saitohin polymorphism and executive dysfunction in schizophrenia

Saitohin (STH) is an intronless gene nested within the human tau gene, which contains a single nucleotide polymorphism (A/G), suggested to be involved in the physiopathology and clinical course of several neurodegenerative and neuropsychiatric diseases. Recently, an association between this polymorphism and frontal hypoperfusion and clinical prognosis in frontotemporal dementia was reported. The present study sought to evaluate the possible role of the STH polymorphism as a concurring factor of cognitive decline in schizophrenia, a disease sharing both early psychotic manifestations, a core deficit of executive functions and hypofrontality with frontotemporal lobe dementia. 220 clinically stabilized patients with schizophrenia were assessed with the Wisconsin Card Sorting Test (WCST) for evaluation of executive functions and compared for STH allele frequency with 48 patients affected by frontotemporal dementia and 47 healthy subjects. There was no significant difference in allelic distribution between the healthy controls and all other groups, while we observed a significantly greater frequency of G allele among both patients with frontotemporal dementia (p = 0.037) and schizophrenia patients with poor performances of WCST (p = 0.044), compared to schizophrenia patients with best WCST performances. Among the patients with schizophrenia, stratified for age and gender, the STH polymorphism resulted in a significant predictor of WCST performance (p = 0.007). These results suggest a possible contribution of STH gene products on the heterogeneity of core frontal executive functions deterioration, probably through complex interactions with mechanism involved in neurodevelopment and neurodegeneration.

Is There Evidence for Late Cognitive Decline in Chronic Schizophrenia?

Schizophrenia (SZP) has been historically referred to as "dementia praecox" because of the recognition that its onset is associated with deficits in memory, attention and visuospatial orientation. We wondered whether there is evidence for additional cognitive decline late in the course of chronic SZP. This review examined the evidence (1) for cognitive decline late in the course of chronic SZP, (2) for how often the late cognitive decline occurs, and (3) whether the cognitive decline in late-life SZP is related to pathophysiology of SZP versus the superimposition of another type of dementia. A PUBMED search was performed combining the MESH terms schizophrenia and dementia, cognitive decline, cognitive impairment and cognitive deficits. A manual search of article bibliographies was also performed. We included longitudinal clinical studies employing standard tests of cognition. Cross-sectional studies and those that did not test cognition through standard cognitive tests were excluded. The initial search produced 3898 studies. Employing selection criteria yielded twenty-three studies. Our data extraction tool included the number of patients in the study, whether a control group was present, the age of patients at baseline and follow-up, the study setting (inpatients versus outpatients), the cognitive tests employed, study duration, and results. Only three longitudinal studies tested for dementia using Diagnostic and statistical manual of mental disorder (DSM) or International classification of disease (ICD) criteria and compared them to controls: two studies demonstrated an increase in the prevalence of dementia and one did not. Twenty longitudinal studies tested for one or more cognitive domains without employing standard criteria for dementia: twelve studies demonstrated a heterogeneous pattern of cognitive decline and eight did not. Studies generally did not control for known risk factors for cognitive impairment such as education, vascular risk factors, apolipoprotein (ApoE) genotype and family history. The evidence for late cognitive decline in SZP is mixed, but, slightly more studies suggest that it occurs. If it occurs, it is unclear whether it is related to SZP or other risks for cognitive impairment. Hence, prospective, longitudinal, controlled studies are needed to confirm that there is progressive cognitive decline in chronic SZP which occurs independent of other risk factors for cognitive impairment.

Raising GABA Levels Might Undo Cognitive Defect in Schizophrenia

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessRaising GABA Levels Might Undo Cognitive Defect in SchizophreniaJoan Arehart-TreichelJoan Arehart-TreichelSearch for more papers by this authorPublished Online:7 May 2010https://doi.org/10.1176/pn.45.9.psychnews_45_9_020AbstractThe neurotransmitter GABA is decreased in the brains of individuals with schizophrenia, researchers reported in the March 10 Journal of Neuroscience.They used a technique called magnetic resonance spectroscopy to measure the levels of GABA in the visual cortex of 13 subjects with schizophrenia and 13 demographically matched control subjects. GABA concentration in the schizophrenia subjects was 10 percent less than in the control group.Furthermore, the researchers found a highly significant link between the GABA deficiency in the visual cortex of the schizophrenia subjects and a particular cognitive defect—a visual perception problem already known to be present in individuals with schizophrenia. The problem is called orientation-specific surround suppression, a behavioral measure of visual inhibition thought to be dependent on GABA neurotransmission.So it looks as if a GABA deficiency may be responsible for this cognitive defect in schizophrenia and perhaps for others as well, the researchers believe.Or as Cameron Carter, M.D., senior author and a professor of psychiatry at the University of California, Davis, put it, “This work provides tremendous support for targeting the GABA system for treatment of cognitive decline in schizophrenia.”Still another positive aspect of their study, Jong Yoon, M.D., lead investigator and an assistant professor of clinical psychiatry at the university, explained, is “that not only have we found that GABA is deficient in living [schizophrenia] subjects, but we have developed a model system with which we can evaluate GABA function and evaluate interventions targeting GABA function.” In other words, the hope is that a drug that acts on GABA might be found to correct some of the cognitive deficiencies that accompany schizophrenia, since antipsychotic medications currently on the market have a modest effect at best on cognition, he said.There are already some indications that drugs that act on GABA might be of benefit in this regard. A small pilot study headed by David Lewis, M.D., a professor of psychiatry and neuroscience at the University of Pittsburgh, and published in the December 2008 American Journal of Psychiatry found that subjects with schizophrenia performed better on cognitive tests after being given a particular GABA agonist than after being given a placebo. And an Israeli company reported last year that subjects with schizophrenia who received an investigational drug that acts on GABA receptors experienced a significantly greater improvement in cognition than did subjects with schizophrenia who received a placebo (Psychiatric News, November 20, 2009).The study was funded by NARSAD and the National Institute of Mental Health.An abstract of “GABA Concentration Is Reduced in Visual Cortex in Schizophrenia and Correlates With Orientation-Specific Surround Suppression” is posted at <www.jneurosci.org/cgi/content/abstract/30/10/3777>. ISSUES NewArchived

Cognitive decline in schizophrenia from childhood to midlife: A 33-year longitudinal birth cohort study

BackgroundWe examined cognitive deficits before and after onset of schizophrenia in a longitudinal study that: 1) covers a long time interval; 2) minimizes test unreliability by including the identical measure at both childhood and post-onset cognitive assessments; and 3) minimizes bias by utilizing a population-based sample in which participants were selected neither for signs of illness in childhood nor for being at risk for schizophrenia. MethodsParticipants in the present study, Developmental Insult and Brain Anomaly in Schizophrenia (DIBS), were ascertained from an earlier epidemiologic study conducted in Oakland, CA. The original version of the Peabody Picture Vocabulary Test (PPVT), a test of receptive vocabulary, was administered at age 5 or 9 and repeated as part of the DIBS study at an average age of 40. There were 10 DIBS cases with DSM-IV schizophrenia or schizoaffective disorder and 15 demographically similar DIBS controls with both child and adult PPVT scores. ResultsCases scored significantly lower than controls in childhood (d=0.95) and adulthood (d=1.67). Residualized scores indicating the number of SDs above or below one's predicted adult score revealed a mean case–control difference of −1.51SDs, consistent with significant relative decline over time among the cases (p<0.0013). ConclusionsIn this prospective study, individuals who developed adult schizophrenia manifested impaired receptive vocabulary during childhood and further relative deterioration (or lack of expected improvement) between childhood and midlife. Limitations should also be acknowledged, including the small sample size and the fact that we cannot be certain when the continued deterioration took place.

DTNBP1 genotype influences cognitive decline in schizophrenia

Objective Intellectual decline is common in schizophrenia and predicts functional outcome. While many patients undergo intellectual decline that typically predates the onset of symptoms, few studies have investigated the underlying mechanism through which this occurs. The current study assessed the relationship between intellectual decline in schizophrenia and genetic variation in dysbindin-1 ( DTNBP1). Methods We assessed cognitive decline in 183 Caucasian patients with schizophrenia using a proxy measure of premorbid IQ with which current general cognitive ability ( g) was compared. We then tested for a relationship between the risk haplotype identified in previous work (CTCTAC) and intellectual decline. Results We found that carriers of the CTCTAC haplotype, demonstrated a significantly greater decline in IQ as compared with non-carriers ( p = 0.05). Conclusions These data suggest that DTNBP1 influences the severity of intellectual decline in schizophrenia and may represent one underlying cause for heterogeneity in cognitive course.

Are deficits in executive sub-processes simply reflecting more general cognitive decline in schizophrenia?

Background Schizophrenia is associated with both global and specific cognitive deficits. We sought to investigate whether deficits in executive subcomponents differed in their relationship to global cognitive impairments. Method 95 patients were classified according to pre-morbid and current general cognitive ability as having either (a) intact pre-morbid and current general cognitive ability; (b) intact pre-morbid but deteriorated current ability, and (c) deteriorated both pre-morbid and current cognitive ability. All patients completed measures of verbal and spatial working memory, sustained selective attention, attentional set sifting, and inhibitory control. Results Deficits on both measures of working memory were associated with general cognitive ability. None of the attentional control deficits observed were associated with general ability. Further, spatial working memory deficits were also associated with more severe negative symptoms. Conclusions These results provide further evidence of the discreet nature of attentional deficits in schizophrenia. By contrast, this study suggests that working memory deficits may to some extent index more general cognitive decline. Awareness of such overlap is important for schizophrenia genetics studies where working memory measures has been used to index supposedly discreet aspects of cognitive dysfunction.

Thought disorder, pragmatic language impairment, and generalized cognitive decline in schizophrenia

Background Schizophrenia is associated with pragmatic language impairment (PLI), a reduced ability to communicate intention in a rule-governed fashion. Two explanations for PLI include that PLI is equivalent to thought disorder and that PLI is secondary to generalized cognitive decline. Objectives The aims of this study were to demonstrate PLI in schizophrenia and to test which of these explanations best accounts for the relationships among thought disorder, PLI, and generalized cognitive decline. Method Schizophrenia ( n=20) and control ( n=26) participants provided speech samples that were scored for thought disorder (type–token ratio and Cloze procedure) and PLI [Profile of Pragmatic Impairment in Communication (PPIC)]. Generalized cognitive decline was determined from discrepancies between current and premorbid verbal IQ. Results Patients with schizophrenia exhibited significant PLI and generalized cognitive decline. There was no evidence of an association between thought disorder and PLI. Moreover, generalized cognitive decline predicted PLI ( r 2=0.33 to 0.59) but not thought disorder ( r 2=0.02 to 0.06). Conclusions The results conformed to a predicted pattern of associations based on the notion that PLI in schizophrenia is secondary to generalized cognitive decline.

Post-onset cognitive decline in schizophrenia is relatively selective for executive-abstraction function

Post-onset cognitive decline in schizophrenia is relatively selective for executive-abstraction function

Global cognitive decline in schizophrenia with remission of symptoms?

The relation of symptoms to cognitive dysfunction in schizophrenia is still controversial. This study was aimed (i) at verifying if a homogeneous sample of 10 young treated outpatients in remission from psychotic symptoms displays a characteristic pattern of cognitive dysfunction and (ii) at testing the issue of a general cognitive impairment. The neuropsychological performance of the patients was confronted with a large control group by means of Equivalent Scores, a normative method widely used in Italy, which allows direct, reliable comparison between tests and between patients. We found that our patients, as a group, were affected by a basic activation deficit in attention and by a semantic impairment. These deficits in symptom-free patients could indicate that their brains are in some ways working differently from those of normal controls and that this pattern is not necessarily linked to psychotic symptoms: their neuropsychological impairment might reflect a basic difference in the way of processing information that is always present and is independent of general intellectual decay.