Mismatch negativity indexes illness-specific impairments of cortical plasticity in schizophrenia: a comparison with bipolar disorder and Alzheimer's disease.

Cognitive impairment is an important predictor of functional outcome in patients with schizophrenia, yet its neurobiology is still incompletely understood. Neuropathological evidence of impaired synaptic connectivity and NMDA receptor-dependent transmission in superior temporal cortex motivated us to explore the correlation of in vivo mismatch negativity (MMN) with cognitive status in patients with schizophrenia. MMN elicited in a roving stimulus paradigm displayed a response proportional to the number of stimulus repetitions (memory trace effect). Preliminary evidence in patients with chronic schizophrenia suggests that attenuation of this MMN memory trace effect was correlated with the degree of neuropsychological memory dysfunction. Here we present data from a larger confirmatory study in patients with schizophrenia, bipolar disorder, probable Alzheimer's disease and healthy controls. We observed that the diminution of the MMN memory trace effect and its correlation with memory impairment was only found in the schizophrenia group. Recent pharmacological studies using the roving paradigm suggest that attenuation of the MMN trace effect can be understood as abnormal modulation of NMDA receptor-dependent plasticity. We suggest that the convergence of the previously identified synaptic pathology in supragranular cortical layers with the intracortical locus of MMN generation accounts for the remarkable robustness of MMN impairments in schizophrenia. We further speculate that this layer-specific synaptic pathology identified in supragranular neurons plays a pivotal computational role, by weakening the encoding and propagation of prediction errors to higher cortical modules. According to predictive coding theory such breakdown will have grave implications not only for perception, but also for higher-order cognition and may thus account for the MMN-cognition correlations observed here. Finally, MMN is a sensitive and specific biomarker for detecting the early prodromal phase of schizophrenia and is well suited for the exploration of novel cognition-enhancing agents in humans.

Fibrillary astrocytes are decreased in the subgenual cingulate in schizophrenia.

Decreases in astrocyte density and in glial fibrillary acid protein (GFAP) mRNA in the anterior cingulate cortex have been reported changed in mood and affective disorders. Our study examines the relative density and frequency of fibrillary and gemistocytic astrocytes in the white matter of the subgenual cingulate cortex in 11 schizophrenia, 16 bipolar disorder, 20 major depression and 20 normal control cases. Serial coronal sections were stained with H&E for anatomical guidance and GFAP immunohistochemistry for astrocyte identification. Astrocyte density was measured using systematic anatomical distinctions and randomised counting methods previously reported. Astrocytes were classified as fibrillary or gemistocytic based on staining and morphometric criteria and were measured in the crown and base of the gyral white matter. Fibrillary astrocytes were decreased in the base of the cingulate white matter in schizophrenia (p = 0.046), with no change in the density of gemistocytic astrocytes. There was no change in density of gemistocytic astrocytes. This suggests that the previously reported decrease in astrocytes in schizophrenia in the subgenual cingulate is accounted for only by a change in fibrillary astrocytes. With recent findings suggesting fibrillary astrocytes regulate synaptic glutamate this morphological change may relate to disregulation of function of the subgenual cingulate cortex.

Name relearning in elderly patients with schizophrenia: episodic and temporary, not semantic and permanent.

INTRODUCTION: Recent reports of lexical-semantic deficits in patients with schizophrenia (Laws, Al-Uzri, & Mortimer, 2000; Laws, McKenna, & Kondel, 1998) suggest that younger patients have problems accessing intact memories and older patients show apparent "loss" of the lexical-semantic memory representations themselves. METHODS: Picture naming for everyday items was examined in a unique series of elderly patients with schizophrenia (n = 10) with a mean illness duration of 45.5 years; and compared with that in patients with probable Alzheimer's disease (n = 18) and elderly healthy controls (n = 27). Naming consistency across time was used as an indicator of whether the schizophrenic patients had difficulty accessing representations or a loss of the representations themselves. Finally, we examined the ability of the schizophrenic patients to relearn the names of unnamed items across four weekly retraining sessions and to retain them at a one month follow-up. RESULTS: The elderly schizophrenic patients were as anomic as patients with probable Alzheimer's disease. Consistency analysis revealed that the patients had storage deficits. Analysis of patient error types was consistent with a semantic deficit. Finally, the schizophrenic patients showed significant improvement with relearning, but this was not maintained at follow-up. CONCLUSIONS: Elderly patients with schizophrenia show a profound and stable anomia. Although name relearning induced some significant gains in naming, these were short-term and reflect episodic rather than semantic reinstatement of representations. Implications for cognitive remediation are discussed.

Down-regulation of Dickkopf 3, a regulator of the Wnt signalling pathway, in elderly schizophrenic subjects.

The aetiology of schizophrenia is complex and the pathological mechanisms involved are still not fully understood. The aim of this project was to gain insight into the underlying molecular changes occurring in schizophrenia through the analysis of gene expression. Using suppression subtractive hybridization to isolate differentially expressed genes in superior temporal cortex (BA22), we detected one prominent sequence with reduced expression in schizophrenia and represented in at least nine clones. This was then selected for further validation. This 190-bp partial transcript showed identity to part of the Dickkopf-3 (Dkk3) gene sequence. Differential expression was initially confirmed in BA22 by slot blot hybridization where expression was decreased by 35% (p < 0.026). These results were further authenticated in a larger panel (12 control and 11 schizophrenia cases) using SYBR Green I real-time quantitative RT-PCR, in which a 41% decrease in expression of Dkk3 mRNA in schizophrenia was obtained (p < 0.012). Furthermore, using in situ hybridization, Dkk3 mRNA was shown to be abundantly expressed in cortical neurones, with prominent expression in layers II/III and V/VI of BA22. Dkk3 belongs to a novel family of Dkk proteins, which have been shown to be potent inhibitors of the neurodevelopmental wingless (Wnt) signalling pathway, and is therefore a putative candidate for further investigation into the aetiology of schizophrenia.

Mismatch negativity potentials and cognitive impairment in schizophrenia.

Cognitive impairment in schizophrenia is an important predictor of clinical and social outcome. In this preliminary study, the correlation between cognitive status and deficits in mismatch negativity (MMN) generation was explored. The MMN response to tone duration deviants was recorded using a new stimulation protocol with continuously changing ('roving') standard stimuli in order to measure the effect of standard repetitions on MMN (memory trace effect). Cognitive status of the patient group (n=28) was assessed using neuropsychological screening. Healthy participants (n=20) served as age-matched comparison group. In patients, MMN amplitude in frontal electrodes as well as the MMN memory trace effect was diminished compared to controls. While both measures were inversely related to patient's age and disease severity, only the MMN memory trace effect was robustly correlated with the degree of neuropsychological impairment. This suggests that ERP measures of auditory system adaptability more appropriately characterise the pathophysiological processes underlying cognitive impairment in schizophrenia than static measures of ERP magnitude.

Intellectual differences between schizophrenic patients and normal controls across the adult lifespan.

A debate persists about whether IQ declines during the duration of schizophrenia or whether an early deficit remains static across the lifespan. To examine this, we measured estimated current IQ (Quick Test Revised: QTR) and estimated premorbid IQ (National Adult Reading Test: NART) in schizophrenic patients (n=110) and matched healthy controls (n=71) across a wide age range (20-88). Age correlated negatively with NART and QTR IQ for schizophrenic patients, but not for controls. A subset of 23 schizophrenic patients was also retested on the NART after 4 years to determine NART stability and they showed no significant change. We propose that the lower NART IQ in older patients reflects a lower 'starting point' and that this may be related to lower educational opportunities in older patients.

A 28-week comparison of ziprasidone and haloperidol in outpatients with stable schizophrenia.

BACKGROUND: Ziprasidone is a novel antipsychotic with a unique pharmacologic profile. This study compared ziprasidone with the conventional antipsychotic haloperidol in outpatients with stable schizophrenia. METHOD: Three hundred one outpatients with stable chronic or subchronic schizophrenia (DSM-III-R) were randomized and participated in this double-blind, multicenter, parallel-group clinical study comparing flexible-dose oral ziprasidone, 80-160 mg/day (N = 148), with haloperidol, 5-15 mg/day (N = 153), over 28 weeks. Patients were assessed using the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impressions-Severity of Illness scale, the Montgomery-Asberg Depression Rating Scale, the Simpson-Angus Scale, the Barnes Akathisia Scale, and the Abnormal Involuntary Movement Scale. RESULTS: Modal doses at endpoint were 80 mg/day for ziprasidone and 5 mg/day for haloperidol. Improvements in all mean efficacy variables with both ziprasidone and haloperidol were observed. Significantly more patients were categorized as negative symptom responders (> or = 20% reduction in PANSS negative subscale score) in the ziprasidone group (48%) compared with the haloperidol group (33%) (p < .05). Ziprasidone had clear advantages over haloperidol in all evaluations of movement disorders. Changes in body weight were negligible with both treatments. No pattern of laboratory or cardiovascular changes was observed. CONCLUSION: Ziprasidone and haloperidol were both effective in reducing overall psychopathology; ziprasidone demonstrated effective treatment of negative symptoms and was better tolerated than haloperidol. Ziprasidone appears to offer an effective alternative to haloperidol in the long-term treatment of stable outpatients with schizophrenia.

A volumetric biochemical niacin flush-based index that noninvasively detects fatty acid deficiency in schizophrenia.

(1) It is possible to investigate aspects of phospholipid-related signal transduction in humans noninvasively using the niacin skin flush test. (2) Patients with schizophrenia have previously been reported to show a reduced flushing response. (3) The aim of this study was to devise a comprehensive index of cutaneous response to the niacin test, incorporating aqueous methyl nicotinate concentration and time, and to test this index in schizophrenia. (4) A discrete approximation to a continuous volumetric index, which we have named the volumetric niacin response (VNR), was devised. Its value was measured in 27 patients with DSM-IV schizophrenia and 26 age- and sex-matched normal controls. (5) The mean value of the VNR in the patients with schizophrenia (16.26) was significantly smaller than that of 26.77 in the normal controls (P<.0004). (6) With a threshold value for the VNR of 21, the test differentiated well between schizophrenia and normal controls (P=.002) with a sensitivity of 78% and a specificity of 65%. (7) The present results confirm that the flushing response is reduced in schizophrenia, and show that calculation of the VNR is an effective means of allowing the total response in different patients or patient groups to be readily compared.

Impairment in frontal but not temporal components of mismatch negativity in schizophrenia.

Impairment in mismatch negativity (MMN) potentials is a robust finding in schizophrenia. While previous studies suggested that MMN in man is generated by a single dipole source bilaterally in the primary auditory cortex, more recent data modified this assumption by showing differential modulation of MMN components over the frontal and temporal scalp. Here we used a roving standard experiment to record mismatch potentials to tone duration deviants with the aim to detect robust temporal and frontal mismatch components. Fourteen schizophrenic patients with normal intelligence and without overt cognitive deficits and age- and sex-matched controls were studied. In agreement with previous findings MMN recorded from the frontal scalp was markedly attenuated in patients. However, in contrast to previous reports, positive mismatch potentials of normal magnitude were recorded from temporal (mastoid) electrodes. This finding raises the possibility of a selective impairment in multiple mismatch generators in schizophrenia and may lend support for the notion of impaired cortico-cortical connectivity in schizophrenia.