Correlation between ß-amyloid deposits revealed by BF-227-PET imaging and brain atrophy detected by voxel-based morphometry-MR imaging: a pilot study.

OBJECTIVE: The purpose of this study was to investigate whether ß-amyloid (Aß) deposition was associated with local atrophy of corresponding areas in the brain. METHODS: [11C]2-[2-(2-Dimethylaminothiazol-5-yl) ethenyl-6-[2-(fluoro)ethoxy]benzoxazole (BF-227)-PET, MRI and neuropsychological tests were carried out on 56 subjects, out of which 21 were patients with Alzheimer's disease (AD), 20 were patients with mild cognitive impairment (MCI) and 15 were normal controls (NC). The BF-227 uptake in each local brain region was set up with automated anatomical labeling atlas using Wake Forest University PickAtlas software and local standardized uptake value ratios of BF-227 were calculated as the average value of right and left using the MRIcron software. RESULTS: Group comparisons of Aß deposition as determined by BF-227 uptake using PET imaging showed no significant differences between MCI and AD. Aß deposition was significantly higher in MCI and AD than in NC. The correlation analysis between local Aß deposition and gray matter atrophy showed that in AD, the Aß deposition in the inferior temporal gyrus was strongly related to the gray matter atrophy in this region. On the contrary, the Aß deposition in the precuneus was associated with the atrophy in the right occipital-temporal region. In the NC, the Aß deposition in the inferior temporal gyrus was associated with the atrophy in the precuneus. CONCLUSION: In the AD, the relationship between the Aß deposition and local atrophy is area-dependent. In NC, Aß deposition in the inferior temporal gyrus correlated to the atrophy in the precuneus.

Relationship of psychopathological symptoms and cognitive function to subjective quality of life in patients with chronic schizophrenia.

AIMS: The purpose of the present study was to examine the extent of the effects of psychopathological symptoms and cognitive function on quality of life (QOL) in patients with chronic schizophrenia. METHODS: Data were obtained using the Japanese Schizophrenia Quality of Life Scale (JSQLS), Positive and Negative Syndrome Scale (PANSS), Wisconsin Card-Sorting Test (WCST) Keio version, and Continuous Performance Test (CPT) for 52 schizophrenia patients. RESULTS: Stepwise regression analysis showed that PANSS depression/anxiety factors predicted JSQLS psychosocial conditions and motivation/energy, and that WCST Categories Achieved predicted JSQLS symptoms/side-effects. CONCLUSIONS: Psychopathological symptoms and cognitive function affect subjective QOL in patients with schizophrenia. If the final goal is treatment that improves QOL in a manner that patients themselves are aware of, clinicians probably need to consider a treatment strategy that improves depression/anxiety symptom.

The Disrupted-in-Schizophrenia-1 Ser704Cys polymorphism and brain morphology in schizophrenia.

The Disrupted-in-Schizophrenia-1 (DISC1) polymorphism is a strong candidate for a schizophrenia-susceptibility gene as it is widely expressed in cortical and limbic regions, but the effect of its genotype variation on brain morphology in schizophrenia is not well known. This study examined the association between the DISC1 Ser704Cys polymorphism and volumetric measurements for a broad range of fronto-parietal, temporal, and limbic-paralimbic regions using magnetic resonance imaging in a Japanese sample of 33 schizophrenia patients and 29 healthy comparison subjects. The Cys carriers had significantly larger volumes of the medial superior frontal gyrus and short insular cortex than the Ser homozygotes only for healthy comparison subjects. The Cys carriers tended to have a smaller supramarginal gyrus than the Ser homozygotes in schizophrenia patients, but not in healthy comparison subjects. The right medial superior frontal gyrus volume was significantly correlated with daily dosage of antipsychotic medication in Ser homozygote schizophrenia patients. These different genotype effects of the DISC1 Ser704Cys polymorphism on the brain morphology in schizophrenia patients and healthy comparison subjects suggest that variation in the DISC1 gene might be, at least partly, involved in the neurobiology of schizophrenia. Our findings also suggest that the DISC1 genotype variation might have some relevance to the medication effect on brain morphology in schizophrenia.

An association between serotonin receptor 3B gene (HTR3B) and treatment-resistant schizophrenia (TRS) in a Japanese population.

Genetic factors are thought to be involved in the development of treatment-resistant schizophrenia (TRS). Since several antipsychotic drugs inhibit the release of neurotransmitters via the serotonin receptors 3 (5-HT3), a dysfunction of this kind of receptor might be associated with the development of TRS. Thus, single-marker and haplotype analyses of the tag-single nucleotide polymorphisms (SNPs) of the 5-HT3B subunit gene (HTR3B) were performed in TRS (n = 101) and non-TRS (n = 244) patients. The deletion allele at the 3 bp-insertion/deletion polymorphism site (-100_-102delAAG) located in the putative HTR3B promoter region is significantly more frequent in the TRS group than the insertion allele by a single-marker comparison (p = 0.031). In addition, luciferase promoter assays showed that the deletion allele exhibited significantly higher transcriptional activity than the insertion allele in COS7 cells (p < 0.05). These results suggest that HTR3B is involved in the development of TRS in the Japanese population.

The association of genotypic combination of the DRD3 and BDNF polymorphisms on the adhesio interthalamica and medial temporal lobe structures.

Abnormal neurodevelopment in midline structures such as the adhesio interthalamica (AI), as well as in the medial temporal lobe structures has been implicated in schizophrenia, while its genetic mechanism is unknown. This magnetic resonance imaging study investigated the effect of the genotypic combination of the dopamine D3 receptor (DRD3) Ser9Gly and brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms on the AI length and volumetric measures of the medial temporal lobe structures (amygdala, hippocampus, and parahippocampal gyrus) in 33 schizophrenia patients and 29 healthy controls. The subjects with a combination of the Ser/Ser genotype of DRD3 and Met-containing genotypes of BDNF (high-risk combination) had a shorter AI than those without it in the healthy controls, but not in the schizophrenia patients. The subjects carrying the high-risk combination had a smaller posterior hippocampus than those without it for both diagnostic groups. These genotypic combination effects on brain morphology were not explained by the independent effect of each polymorphism. These findings suggest the effect of gene-gene interaction between the DRD3 and BDNF variations on brain morphology in midline and medial temporal lobe structures, but do not support its specific role in the pathogenesis of schizophrenia.

Relationship between three serotonin receptor subtypes (HTR3A, HTR2A and HTR4) and treatment-resistant schizophrenia in the Japanese population.

The proportion of treatment-resistant schizophrenia (TRS) has been estimated as 20-40% in the schizophrenic patients. Genetic factors are considered to be involved in the development of this condition. Serotonin subtypes are hypothesized to be the candidate genes. In the present study, single marker and haplotype analyses between several mutations of serotonin receptor subtypes (HTR2A, HTR3A and HTR4) and TRS (TRS=101, NON-TRS=239) were performed to determine a possible relationship with the development of TRS. Additionally, we also compared the daily neuroleptic dosage among each genotype. No significant association was observed between TRS and each allele, genotype, and haplotype. However, the daily neuroleptic dosage that patients had been receiving during their maintenance therapy was significantly higher in patients with the T/T genotype of HTR3A polymorphism (rs1062613, p=0.041). The present results support further research to examine the relationship between HTR3A polymorphism and the development of TRS in the Japanese population.

An association study of tachykinin receptor 3 gene with schizophrenia in the Japanese population.

The tachykinin receptor 3 (TACR3) gene encodes the neurokinin3 (NK3) receptor. Animal studies showed that agonist-induced stimulation of the NK3 receptor leads to the excessive release of dopamine in the ventral and dorsal striatal and prefrontal cortical regions. Data from clinical trials of selective NK3 receptor antagonists in schizophrenia have shown significant improvement in positive symptoms. We performed an association study of the TACR3 gene in the Japanese population of 384 schizophrenic patients and 384 controls. Nine single nucleotide polymorphisms were genotyped using TaqMan assays and polymerase chain reaction-restriction fragment length polymorphism method. No significant association between schizophrenia and these single nucleotide polymorphisms was observed in single-marker and haplotype analyses. Our results suggest that TACR3 is unlikely to be related to the development of schizophrenia in the Japanese population.

Association of SOX10 with schizophrenia in the Japanese population.

BACKGROUND: Microarray studies of schizophrenic brains revealed decreases in the expression of myelin and oligodendrocyte-related genes. Of these genes, sex-determining region Y-box 10 (SOX10) is a major transcription factor modulating the expression of proteins involved in neurogenesis and myelination. The SOX10 gene is located on chromosome 22q13.1, a region repeatedly reported to show positive signals in linkage studies on schizophrenia. OBJECTIVE: This study was conducted to clarify the exact role of SOX10 in the pathophysiology of schizophrenia. METHODS: We performed an association analysis of SOX10 in a Japanese population of 915 schizophrenic patients and 927 controls. Genotyping was carried out using polymerase chain reaction restriction fragment length polymorphism. MAIN RESULTS: One single nucleotide polymorphism of the SOX10 gene (rs139,887) was selected as a haplotype tag single nucleotide polymorphism using 96 controls. A significant association was observed in the genotype and allelic frequency of this single nucleotide polymorphism between schizophrenic patients and controls (P=0.025 and P=0.009, respectively). Especially, a significant association was found in male patients, but not female patients. We also performed a mutational search of the whole coding region, branch site, and promoter region of SOX10 in 96 schizophrenic patients, but no potential functional polymorphisms were detected. CONCLUSION: This study suggests that the SOX10 gene is related to the development of schizophrenia in the Japanese population.

Association study between the transferrin gene and schizophrenia in the Japanese population.

Several lines of evidence, including diffusion tensor imaging and microarray studies, indicate that abnormalities in myelination play an important role in the pathophysiology of schizophrenia. Of myelin and oligodendrocyte-related genes, a significant decrease in the mRNA levels of transferrin in schizophrenics has been reported by both microarray and quantitative polymerase chain reaction studies. We performed an association analysis of the transferrin gene in a Japanese population of 384 schizophrenic patients and 384 controls. Six single nucleotide polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism and a TaqMan assay. No significant differences in genotype, allele, or haplotype frequencies of the six single nucleotide polymorphisms were observed between schizophrenic patients and controls. The present results suggest that the transferrin gene is not related to the development of schizophrenia in the Japanese population.

Gap junction coding genes and schizophrenia: a genetic association study.

The aim of this study was to evaluate the association of genes that encode gap junction forming proteins and schizophrenia. Representative genetic candidates (Panx2 and Cx36) from two families of gap junction genes were selected for analysis. According to the present findings these genes represent both functional and positional candidates for schizophrenia. The sample was comprised of 381 schizophrenic patients, and the same number of matched controls was tested in this study in order to evaluate the possible influence of the aforementioned genes on the pathogenesis of schizophrenia. Four SNPs in the case of Panx2 and two SNPs in the case of Cx36 were selected for analysis. Allele-, genotype- and haplotype-wise association did not yield statistically significant results. These data do not suggest that Panx2 or Cx36 could increase the risk of schizophrenia in the Japanese population.

Association between gene polymorphisms of SLC22A3 and methamphetamine use disorder.

BACKGROUND: Methamphetamine (MAP) is one of the most frequently used illegal substances in Japan, and family and twin studies have suggested that genetic factors contribute to psychostimulant dependence, including MAP dependence. Organic cation transporter 3 (OCT3) has been reported to be involved in the disposition of MAP as well as MAP-induced behavioral changes in animals. Moreover, SLC22A3 (which encodes OCT3) is a candidate gene for MAP dependence because it is located within a chromosomal region associated with substance dependence. METHODS: Using 96 healthy control subjects, linkage disequilibrium (LD) within the SLC22A3 was investigated, and 5 single-nucleotide polymorphisms (SNPs) were selected as haplotype tag SNPs to search for an association with MAP dependence. Single-marker analyses and haplotype analyses of these SNPs were performed in 213 subjects with MAP dependence and 443 healthy controls. RESULTS: SLC22A3 polymorphisms were not significantly associated with MAP dependence in any of the single-marker and haplotype analyses. When subjects with MAP dependence were divided into polysubstance and single-MAP users, genotype and allele frequency of SNP2 (p=0.024, p=0.011, respectively), allele frequency of SNP3 (p=0.037), and haplotypic frequencies for these 2 SNPs (p=0.0438) differed significantly between groups. CONCLUSIONS: These results suggest that polymorphisms of SLC22A3 are related to the development of polysubstance use in Japanese patients with MAP dependence.

Personality of seasonal affective disorder analyzed by Tri-dimensional Personality Questionnaire.

BACKGROUND: Although there have been numerous reports in personality of mood disorders, there have been few reports in regard with personality of winter seasonal affective disorder (SAD). Furthermore, no reports have been published concerning summer SAD personality characteristics. Thus, this study was conducted to assess the personality of winter and summer SAD using Tri-dimensional Personality Questionnaire (TPQ) that have been used in a variety of mental disorders. METHODS: A total of 6135 Japanese were evaluated with TPQ, the Seasonal Pattern Assessment Questionnaire (SPAQ) and the Self-rating Depression Scale (SDS). Winter, summer and non-SAD groups were classified by SPAQ. We compared the difference of personality trait among these three groups in consideration of gender, age and SDS score influence. RESULTS: Winter SAD demonstrated higher "Novelty Seeking" and "Harm Avoidance"; summer SAD showed higher "Harm Avoidance" than the non-SAD group. "Harm Avoidance" in both SAD groups was re-analyzed using SDS score as a covariate, and "Novelty Seeking" in winter SAD using age as a covariate. As a result, the significance of high "Novelty Seeking" and high "Harm Avoidance" in winter SAD was excluded. However, "Harm Avoidance" remained the significant difference between summer and non-SAD. LIMITATION: SAD was diagnosed only by SPAQ and not by interview. The state-dependency of "Harm Avoidance" was not confirmed in identical patients over lapse of time. CONCLUSION: Patients with winter SAD have high "Harm Avoidance" dependent on the depressive state that is in accordance with non-seasonal depression. Patients with summer SAD have high "Harm Avoidance" possibly independent from the depressive state.