Human dermal fibroblasts in psychiatry research.

In order to decipher the disease etiology, progression and treatment of multifactorial human brain diseases we utilize a host of different experimental models. Recently, patient-derived human dermal fibroblast (HDF) cultures have re-emerged as promising in vitro functional system for examining various cellular, molecular, metabolic and (patho)physiological states and traits of psychiatric disorders. HDF studies serve as a powerful complement to postmortem and animal studies, and often appear to be informative about the altered homeostasis in neural tissue. Studies of HDFs from patients with schizophrenia (SZ), depression, bipolar disorder (BD), autism, attention deficit and hyperactivity disorder and other psychiatric disorders have significantly advanced our understanding of these devastating diseases. These reports unequivocally prove that signal transduction, redox homeostasis, circadian rhythms and gene*environment (G*E) interactions are all amenable for assessment by the HDF model. Furthermore, the reported findings suggest that this underutilized patient biomaterial, combined with modern molecular biology techniques, may have both diagnostic and prognostic value, including prediction of response to therapeutic agents.

Neutrophils are required for both the sensitization and elicitation phase of contact hypersensitivity.

Allergic contact dermatitis and its animal model, contact hypersensitivity (CHS), are T cell-mediated inflammatory skin diseases induced by contact allergens. Though numerous cellular and molecular players are known, the mechanism of chemical-induced sensitization remains poorly understood. Here, we identify neutrophils as crucial players in the sensitization phase of CHS. Genetic deficiency of neutrophils caused by myeloid-specific deletion of Mcl-1 or antibody-mediated depletion of neutrophils before sensitization abrogated the CHS response. Neutrophil deficiency reduced contact allergen-induced cytokine production, gelatinase release, and reactive oxygen species production in naive mice. Mast cell deficiency inhibited neutrophil accumulation at the site of sensitization. In turn, neutrophils were required for contact allergen-induced release of further neutrophil-attracting chemokines, migration of DCs to the draining lymph nodes, and priming of allergen-specific T cells. Lymph node cells from mice sensitized in the absence of neutrophils failed to transfer sensitization to naive recipients. Furthermore, no CHS response could be induced when neutrophils were depleted before elicitation or when normally sensitized lymph node cells were transferred to neutrophil-deficient recipients, indicating an additional role for neutrophils in the elicitation phase. Collectively, our data identify neutrophils to be critically involved in both the sensitization and elicitation phase of CHS.

Human cognitive and neuro-psychiatric bio-markers in the cardiac peri-operative patient.

Some of the complexities of surgical interventions include neurological and psychiatric disturbances. Prompt identification and early treatment of these complications are pivotal in achieving excellent clinical results. Recognizing major adverse events such as stroke, seizure or delirium is usually straight-forward, however the discovery of less frequent or more subtle post-operative changes such as cognitive dysfunction might be delayed due to lack of appropriate diagnostic tools. This review summarizes biological markers that can be utilized as surrogates in evaluating surgery-related neuro-psychiatric disorders.

Evaluation of post-surgical cognitive function and protein fingerprints in the cerebro-spinal fluid utilizing surface-enhanced laser Desorption/Ionization time-of-flight mass-spectrometry (SELDI-TOF MS) after coronary artery bypass grafting: review of proteomic analytic tools and introducing a new syndrome.

Cognitive dysfunction following surgery is a common complication, which increases the incidence of other co-morbid conditions, hospital and health-care costs. The reported rate of the occurrence of post-operative cognitive decline varies with different studies, depending on population profile, type of surgery, definition of cognitive disorder and detection methods, design of study, etc. It remains unclear whether these psychiatric signs and symptoms are direct results of the effects of surgery or general anesthesia. Nonetheless they are more frequent after cardiac surgery and are likely to be multi-factorial, but the patho-mechanisms are not yet fully characterized. This communication provides a synopsis of proteomics tools and delineates novel SELDI-TOF results to evaluate biomarkers in this regard. Presented for the first time is a classification of the clinically relevant forms of post-operative cognitive decline with the advent of a novel subclass.

Atheromatosis extent in coronary artery disease is not correlated with apolipoprotein-E polymorphism and its plasma levels, but associated with cognitive decline.

BACKGROUND: Apolipoprotein-E (apoE) ε4 allele is a known risk factor for Alzheimer's disease (AD). Polymorphism of apoE is also one of the most important genetic markers for coronary artery disease (CAD). The allelic variation in the apoE gene has a significant effect on inter-individual variation of lipids and lipoprotein plasma levels as well. This study investigated whether apoE polymorphism affects the plasma levels of apoE and the possible association to CAD extent and cognitive functions. METHODS: Plasma apoE levels and apoE genotypes were evaluated of subjects with normal coronary arteries, and individuals with angiographycally confirmed mild/moderate or severe atheromatosis. The cognitive performance of the volunteers was also measured by mini-mental state examination (MMSE). RESULTS: Out of the 6 expected genotypes, only 5 were detected in participants: E3/3 (56.0%), E3/4 (23.6%), E4/4 (8.2%), E2/4 (3.3%), E2/3 (8.9%). The ε3 allele (72%) was the most frequent, followed by ε4 (22%) and ε2 (6%). No difference was found in plasma levels of either apoE or in apoE genotype frequencies among the groups, however MMSE scores of CAD patients irrespective of their atheromatosis extent were significantly lower than that seen in the normal population. CONCLUSIONS: Although neither apoE plasma levels, nor apoE polymorphism in patients presenting with mild/moderate or severe atheromatosis showed to be associated with CAD severity, the presence of atheromatosis in the heart vessels positively correlated with cognitive dysfunction.

H1 tau haplotype-related genomic variation at 17q21.3 as an Asian heritage of the European Gypsy population.

In this study, we examine the frequency of a 900 kb inversion at 17q21.3 in the Gypsy and Caucasian populations of Hungary, which may reflect the Asian origin of Gypsy populations. Of the two haplotypes (H1 and H2), H2 is thought to be exclusively of Caucasian origin, and its occurrence in other racial groups is likely to reflect admixture. In our sample, the H1 haplotype was significantly more frequent in the Gypsy population (89.8 vs 75.5%, P<0.001) and was in Hardy-Weinberg disequilibrium (P=0.017). The 17q21.3 region includes the gene of microtubule-associated protein tau, and this result might imply higher sensitivity to H1 haplotype-related multifactorial tauopathies among Gypsies.

Unchanged rat brain amyloid precursor protein levels after exposure to benzodiazepines in vivo.

BACKGROUND AND OBJECTIVE: Recent studies emphasize a positive correlation between (cardiac) surgical interventions and increased risk for developing Alzheimer's disease in the late postoperative period. Since amyloid precursor protein and its neurotoxic derivatives play key roles in the development of Alzheimer's dementia, the impact of several agents used in the intra- and perioperative period is examined. METHOD: Amyloid precursor protein concentrations were assessed by semi-quantitative Western-immunoblot in brains of rats following intraperitoneal treatment with diazepam and midazolam. RESULTS: There were no significant changes in the amyloid precursor protein concentrations. CONCLUSION: Both diazepam and midazolam are considered to be relatively safe with respect to amyloid precursor protein metabolism.

Gene expression profile analysis of lymphocytes from Alzheimer's patients.

Since the function and metabolism of peripheral lymphocytes is known to be altered in Alzheimer's disease (AD), a pilot study was carried out to examine differences in gene expression profiles of these cells in 16 AD patients and aged control probands. Using a cDNA microarray representing 3200 distinct human genes, we identified 20 candidate genes whose expression is altered in AD lymphocytes compared with the control probands. Among these were the alpha2C-adrenoreceptor gene, known to regulate blood pressure and learning, the defensin, histocompability complex enhancer-binding protein, carboxypeptidase M, and the Fc fragment of IgE known to be involved in cellular and humoral immune responses. Others, like human cell death protein, TRAIL, and galectin-4 participate in the regulation of apoptosis. Real-time quantitative reverse transcription-polymerase chain reaction analysis was performed in order to confirm the expression changes in AD lymphocytes, and it could detect down-regulation of defensin and alpha2c-adrenoceptor genes, while other genes seemed unaltered in their expression, including heat-shock protein (hsp90), cholesteryl ester transfer protein, and apolipoprotein B100 (apoB). The altered expression profile of these genes might be connected with the previously reported AD-specific lymphocyte abnormalities. It remains to be elucidated, however, how these genes are related to the pathomechanism of dementia and whether the gene expression differences of AD lymphocytes reflect disease traits or stage processes.

Haloperidol attenuates beta-amyloid-induced calcium imbalance in human fibroblasts.

BACKGROUND: Antipsychotics are widely used in the treatment of behavioral and psychological symptoms of dementia. A low frequency of Alzheimer's disease in patients with schizophrenia is reported, and it has been proposed that antipsychotic medications, such as haloperidol, may be responsible. Disruption of intracellular calcium levels is considered to play a key role in beta-amyloid-induced neurotoxicity in Alzheimer's disease. Haloperidol has also been reported to interact with calcium homeostasis through dopamine-2 and sigma-1 receptors, and other, yet unknown mechanisms. OBJECTIVE: Therefore, we investigated whether differences in the basal intracellular free calcium levels of cultured cutaneous fibroblasts--cells that do not express dopamine-2 and sigma-1 receptors--derived from sporadic Alzheimer patients and from age-matched control individuals after haloperidol treatment might be present. METHODS: Intracellular calcium level was measured in Fura-2AM-loaded human fibroblasts by dual wavelength spectrofluorimetry. RESULTS: Alzheimer cells exhibited significantly lower calcium level as compared to the control cultures. Exposure of fibroblasts to beta-amyloid peptide resulted in increased calcium concentration of the control cells, but not of Alzheimer fibroblasts. Co-incubation of cultures with a therapeutic dose of haloperidol blocked the beta-amyloid-induced elevation of calcium. CONCLUSION: This finding indicates that haloperidol efficiently countervails ionic imbalance and suggests that it may serve as a potential agent in alleviating neurotoxic effects of beta-amyloid peptide.

Critical evaluation of cognitive dysfunctions as endophenotypes of schizophrenia.

OBJECTIVE: Cognitive dysfunctions are potential endophenotypes of schizophrenia. The aim of this study was to investigate whether recent evidence indeed suggests that cognitive dysfunctions are potent indicators of specific genetic traits that represent susceptibility for schizophrenia. METHOD: Studies including large, well-defined samples and controlled cognitive assessment have been reviewed. RESULTS: Evidence suggests that schizophrenia patients and their unaffected biological relatives are impaired in several cognitive domains, including working memory, executive functions, sustained attention, verbal episodic memory, processing of visual and auditory stimuli, and smooth pursuit eye movements. However, these impairments are present only in a limited proportion of subjects, showing low specificity and sensitivity and high variability. Linkage with specific genes is weak. CONCLUSION: Although some results are promising, at present cognitive dysfunctions cannot be considered as highly sensitive and specific endophenotypes of schizophrenia.

No evidence for impaired 'theory of mind' in unaffected first-degree relatives of schizophrenia patients.

OBJECTIVE: The aim of this study was to investigate the possibility that 'theory of mind' (ToM) impairments are associated with schizophrenia liability. METHOD: Forty healthy control subjects and 79 first-degree biological relatives of schizophrenia patients (32 siblings and 47 parents) received the Eyes Test, during which subjects are asked to choose the word best describes the mental state of a person whose eyes are depicted on a photograph. RESULTS: The affected relatives (n = 14) performed worse on the Eyes Test compared with the controls (P = 0.0001), whereas the unaffected relatives (n = 65) showed intact performances (P = 0.4). The Eyes Test values did not correlate with age and IQ. There was no significant difference between male and female participants. CONCLUSION: ToM deficits, as measured by the Eyes Test, are not associated with schizophrenia liability.

Patients with schizophreniform disorder use verbal descriptions for the representation of visual categories.

BACKGROUND: Neuropsychological impairment is a common finding in schizophrenia. However, a significant proportion of patients are not impaired in conventional neuropsychological tests. In this study, we investigated whether remitted patients with schizophreniform disorder exhibited dysfunctions in specific cognitive tasks. METHOD: Twenty remitted, highly functioning patients with schizophreniform disorder and 20 control subjects participated in the study. In addition to background neuropsychological evaluation (WAIS-R IQ, Wisconsin Card Sorting Test (WCST), Trail Making B, Rey Osterrieth Complex Figure), subjects received a category learning task. The categories consisted of geometric shapes systematically changing in shape and size. Training included the sequential presentation of category members (visual learning) and verbal description of categories. RESULTS: The patients with schizophreniform disorder had normal IQ, executive functions/psychomotor speed (WCST and Trail Making B) and visual memory (Rey-Osterrieth Complex Figure). In contrast, they displayed impaired categorization performances after visual learning. The performance of the patients improved markedly after verbal description of categories. Verbal knowledge about categories positively correlated with categorization performance in the patients, but not in the controls. CONCLUSIONS: Category learning functions, which include decision-making under uncertainty and feature integration, are impaired in patients with schizophreniform disorder who display normal executive functions and visual memory. These patients may use verbal knowledge as a compensatory strategy in visual tasks.

Dopaminergic contributions to the visual categorization of natural scenes: evidence from Parkinson's disease.

Recent evidence raised the possibility that dopaminergic mechanisms in the neostriatum play an important role in categorization. In this study, we examined the electrophysiological correlates of natural scene categorization in Parkinson's disease (PD), which is characterized by the depletion of dopamine in the neostriatum. Event-related potentials (ERPs) were recorded in PD patients and age-matched control subjects using a natural scene categorization task. Subjects had to decide whether a briefly presented image contained animals or non-animals. In the control group, the mean amplitudes of N1 (150-250 ms) and N2 components (400-600 ms) were more negative for non-animal scenes as compared with stimuli containing animals, whereas P2 (250-350 ms) was more positive for animals. In contrast, in the PD group the mean amplitudes of N1 and N2 components were similar for both animal and non-animal stimuli, and the P2 amplitudes were reduced. In the case of N1 peak latency, there was no between-group difference, whereas the N2 and P2 components were significantly delayed in the PD group. These results suggest that both perceptual (N1) and semantic (N2) processes related to the categorization of natural scenes are specifically impaired in PD. In the temporal domain, the slowed semantic processing is preceded by a relatively normally paced perceptual analysis. These findings are in agreement with the hypothesis emphasizing the importance of striatal dopaminergic mechanisms in classification functions.

Codon 311 (Cys --> Ser) polymorphism of paraoxonase-2 gene is associated with apolipoprotein E4 allele in both Alzheimer's and vascular dementias.

The gene of an esterase enzyme, called paraoxonase (PON, EC.3.1.8.1.) is a member of a multigene family that comprises three related genes PON1, PON2, and PON3 with structural homology clustering on the chromosome 7.(1,2) The PON1 activity and the polymorphism of the PON1 and PON2 genes have been found to be associated with risk of cardiovascular diseases such as hypercholesterolaemia, non-insulin-dependent diabetes, coronary heart disease (CHD) and myocardial infaction.(3-8) The importance of cardiovascular risk factors in the pathomechanism of Alzheimer's disease (AD) and vascular dementia (VD)(9-13) prompted us to examine the genetic effect of PON2 gene codon 311 (Cys-->Ser; PON2*S) polymorphism and the relationship between the PON2*S allele and the other dementia risk factor, the apoE polymorphism in these dementias. The PON2*C and PON2*S allele frequencies were similar in both AD (25% and 75%) and VD groups (23% and 77%), respectively, compared with the controls (27% and 73%). The ratio of the PON2*S carriers was significantly higher among the apoE4 allele carrier AD (27%) and VD (25%) groups than in the control (12%). Our results indicate that the PON2*S and apoE4 alleles have interactive effect on the development of the two most common forms of dementias AD and VD, and further support the hypothesis that cardiovascular factors contribute to the development of AD.

Intact prototype learning in schizophrenia.

In this study, we examined executive functions and visual prototype learning in patients with schizophrenia (n=22) and matched healthy control subjects (n=20). The patients demonstrated marked perseveration in the Wisconsin Card Sorting Test (WCST), whereas they successfully learned prototypes of dot-pattern category exemplars. These findings are against the hypothesis of a pure generalized cognitive dysfunction in schizophrenia, providing preliminary evidence for intact neocortical mechanisms related to perceptual classification functions.

Comparative studies on [Ca2+]i-level of fibroblasts from Alzheimer patients and control individuals.

The accumulation of the beta-amyloid peptide (betaAP) in the brain, produced from the ubiquitously expressed amyloid precursor protein (APP) is a defining feature of Alzheimer's disease (AD). Consistent with studies demonstrating the importance of skin biopsy in the diagnosis of neurodegenerative disorders, we investigated whether differences in intracellular free calcium levels ([Ca2+]i) of cultured cutaneous fibroblasts derived from sporadic AD patients and from age-matched control individuals might be present. [Ca2+]i was measured in Fura-2AM-loaded human fibroblasts by dual wavelength spectrofluorimetry. AD cells exhibited lower [Ca2+]i as compared to the control cultures. Exposure of fibroblasts to betaAP resulted in increased [Ca2+]i of the control cells, but not of AD fibroblasts. Our test could prove useful in supporting the diagnosis of (sporadic) AD in patients suspected of suffering from the disease.

Are Alzheimer's disease patients able to learn visual prototypes?

Recently, controversial results emerged regarding visual prototype learning in Alzheimer's disease (AD). The aim of this study was to elucidate this issue in a larger population of AD patients. The AD patients (N=72) and age-matched healthy control subjects (N=25) learned to recognize and to categorize visual dot patterns. In comparison with the control subjects, the AD patients as a group showed dysfunctions in the recognition task, whereas categorization was relatively spared in their case. Recognition was impaired in patients with mild AD (Mini-Mental score: 18-23) and moderate AD (Mini-Mental score<18), whereas categorization was impaired only in patients with moderate AD. These results suggest that while the medio-temporal/diencephalic explicit memory system is markedly affected even in early AD, the sensory neocortical areas mediating implicit category learning display a sufficient degree of functional capacity until later stages of the disease.

Different trait markers for schizophrenia and bipolar disorder: a neurocognitive approach.

BACKGROUND: The aim of this study was to assess visual information processing and cognitive functions in unaffected siblings of patients with schizophrenia, bipolar disorder and control subjects with a negative family history. METHODS: The siblings of patients with schizophrenia (N = 25), bipolar disorder (N = 20) and the controls subjects (N = 20) were matched for age, education, IQ, and psychosocial functioning, as indexed by the Global Assessment of Functioning scale. Visual information processing was measured using two visual backward masking (VBM) tests (target location and target identification). The evaluation of higher cognitive functions included spatial and verbal working memory, Wisconsin Card Sorting Test, letter fluency, short/long delay verbal recall and recognition. RESULTS: The relatives of schizophrenia patients were impaired in the VBM procedure, more pronouncedly at short interstimulus intervals (14, 28, 42 ms) and in the target location task. Marked dysfunctions were also found in the spatial working memory task and in the long delay verbal recall test. In contrast, the siblings of patients with bipolar disorder exhibited spared performances with the exception of a deficit in the long delay recall task. CONCLUSIONS: Dysfunctions of sensory-perceptual analysis (VBM) and working memory for spatial information distinguished the siblings of schizophrenia patients from the siblings of individuals with bipolar disorder. Verbal recall deficit was present in both groups, suggesting a common impairment of the fronto-hippocampal system.

Remitted schizophrenia-spectrum patients with spared working memory show information processing abnormalities.

Working memory and information processing abnormalities are often reported in schizophrenia. The aim of this study was to examine visual backward masking (BM) functions in remitted schizophrenia-spectrum patients with spared working memory functions. Seventy-two patients with DSM-IV schizophrenia-spectrum disorders were screened using the Wisconsin Card Sorting Test (WCST) and the digit span forward/backward tasks. Patients with spared WCST and digit span performances were selected and administered a spatial working memory test and two BM procedures (target identification and location). The schizophrenia-spectrum group with spared WCST and digit span performances included individuals with schizophreniform disorder (N=11), schizophrenia (N=2), and schizoaffective disorder (N=2). These patients were clinically remitted and demonstrated spared IQ, normal spatial working memory, and relatively high psychosocial functioning. However, there was a significant impairment in the BM procedure, most prominently in the target location task and at short interstimulus intervals. These results suggest that the BM dysfunction is a trait marker of schizophrenia-spectrum disorders and may be present in the absence of working memory abnormalities.