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04/2011: pages 559 - 577; , ISBN: 9780470976739
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Ismail Thanseem,
Kazuhiko Nakamura,
Taishi Miyachi,
Tomoko Toyota,
Satoru Yamada,
Masatsugu Tsujii,
Kenji J Tsuchiya,
Ayyappan Anitha,
Yoshimi Iwayama,
Kazuo Yamada, [......],
Katsuaki Suzuki,
Shiro Suda, Masayoshi Kawai,
Gen-Ichi Sugihara,
Kiyokazu Takebayashi,
Noriyoshi Takei,
Hironobu Ichikawa,
Toshiro Sugiyama,
Takeo Yoshikawa,
Norio Mori
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ABSTRACT: MET receptor tyrosine kinase (MET)-mediated signaling has been implicated in multiple aspects of neocortical and cerebellar neuronal growth and maturation. A promoter functional SNP (rs1858830) that disrupts the transcription of MET has been reported to be strongly associated with autism spectrum disorders (ASD) in the Caucasian population. Here, we performed a trio association study of MET with ASD in Japanese subjects (n=126 trios). Based on the HapMap data on the Japanese population, 15 SNPs were chosen for the association study. One SNP located in intron 1, rs38841, showed a nominal association with autism (p=0.044; OR=1.61) when analyzed using the transmission disequilibrium test. To the best of our knowledge, this is the first replication study of the association of MET with autism, in any non-Caucasian population. Association of rs38841 with autism was further confirmed in 252 Caucasian trios from AGRE (p=0.0006). An interesting observation is that all three SNPs of MET (rs1858830, rs38845 and rs38841) shown to be associated with autism in three independent studies including the present one, are located towards the 5'end of the gene at a span of 9.4 kb. Our results provide further evidence for a possible role of MET in the pathogenesis of ASD.
Neuroscience Research 10/2010; 68(2):137-41. · 2.25 Impact Factor
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ABSTRACT: Fluvoxamine is a selective serotonin reuptake inhibitor widely used in the treatment of depression and other psychiatric diseases. The aim of this study was to assess the clinical impact of cigarette smoking on plasma fluvoxamine concentration in Japanese patients, and evaluate whether the cytochrome P450 (CYP) 1A2 and CYP2D6 genotypes have effects on that concentration. Thirty-two Japanese patients receiving fluvoxamine were enrolled. They were maintained on the same daily dose of fluvoxamine (mean + or - S.D., 109.4 + or - 66.2 mg/d) for at least 4 weeks to obtain the steady-state plasma concentration. The steady-state plasma concentration-to-dose (C/D) ratio of fluvoxamine in patients who smoked (n = 6, 11.8 + or - 6.5 ng/ml/dose) was significantly lower than that in non-smoker patients (n = 26, 22.8 + or - 11.2 ng/ml/dose). There was no significant difference for the C/D ratio of fluvoxamine in patients with CYP1A2 -3860G/G, -3860G/A, and -3860A/A between non-smokers and smokers. Among non-smoker patients, the C/D ratios of fluvoxamine in those with one and two mutated alleles of CYP2D6 were 1.6- and 1.4-fold higher, respectively, than those with no mutated alleles, though the differences among those three genotype groups were not significant. Furthermore, stepwise multiple regression analysis revealed that cigarette smoking and daily dose had significant positive correlations with the plasma concentration of fluvoxamine. Our findings suggest that cigarette smoking has a significant impact on the steady-state plasma concentration of fluvoxamine in Japanese patients.
Biological & Pharmaceutical Bulletin 02/2010; 33(2):285-8. · 1.66 Impact Factor
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ABSTRACT: It is widely accepted that selective serotonin reuptake inhibitors (SSRIs) require 2 to 4 weeks of administration before improvements in emotional symptoms of depression are seen. We evaluated whether early monitoring of Hamilton Rating Scale for Depression (HAMD) scores in patients treated with the SSRI fluvoxamine could predict antidepressant response, and also assessed the relationship between the onset of clinical response following the start of fluvoxamine administration and its plasma concentration. Twelve depressed patients (baseline HAMD score ≥15) received an initial dose of fluvoxamine (50 mg/d) followed by an optimized maintenance dose according to their clinical symptoms after 7 d. HAMD scores and plasma drug concentrations were determined at 7 and 28 d after the first administration. There were 7 responders and 5 non-responders on day 28, as evaluated by HAMD scores. The HAMD score for the responders was significantly lower than that for the non-responders on day 7 (mean±S.D., 11.6±6.1 vs. 26.6±6.5, p=0.006). Thus, the reduction in HAMD score on day 7 was clearly divided between responders and non-responders. On day 28, the plasma concentration of fluvoxamine in responders was lower than that in non-responders (14.2±10.5 ng/ml vs. 44.2±28.1 ng/ml, p=0.051). Furthermore, receiver operating characteristic curve analysis conducted on day 28 revealed an upper concentration threshold of 28.2 ng/ml (p=0.042), with none in the responder group above that level. Our results suggest that HAMD score after the first week of treatment with fluvoxamine and the upper threshold of plasma drug concentration could predict whether a patient is a non-responder.
Biological & Pharmaceutical Bulletin 01/2010; 33(12):1999-2002. · 1.66 Impact Factor
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Ayyappan Anitha,
Kazuhiko Nakamura,
Kazuo Yamada,
Yoshimi Iwayama,
Tomoko Toyota,
Nori Takei,
Yasuhide Iwata,
Katsuaki Suzuki,
Yoshimoto Sekine,
Hideo Matsuzaki, [......],
Shinsuke Matsuzaki,
Kousuke Baba,
Akiko Honda,
Tsuyoshi Hattori,
Shoko Shimizu,
Natsuko Kumamoto,
Mitsuru Kikuchi,
Masaya Tohyama,
Takeo Yoshikawa,
Norio Mori
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ABSTRACT: Disrupted-in-Schizophrenia 1 (DISC1) and its molecular cascade have been implicated in the pathophysiology of major psychoses. Previously, we identified pericentrin 2 (PCNT2) and DISC1-binding zinc finger protein (DBZ) as binding partners of DISC1; further, we observed elevated expression of PCNT2 in the postmortem brains and in the lymphocytes of bipolar disorder patients, compared to controls. Here, we examined the association of PCNT2 with schizophrenia in a case-control study of Japanese cohorts. We also examined the association of DBZ with schizophrenia and with bipolar disorder, and compared the mRNA levels of DBZ in the postmortem brains of schizophrenia, bipolar and control samples. DNA from 180 schizophrenia patients 201 controls were used for the association study of PCNT2 and DBZ with schizophrenia. Association of DBZ with bipolar disorder was examined in DNA from 238 bipolar patients and 240 age- and gender-matched controls. We observed significant allelic and genotypic associations of the PCNT2 SNPs, rs2249057, rs2268524, and rs2073380 (Ser/Arg) with schizophrenia; the association of rs2249057 (P = 0.002) withstand multiple testing correction. Several two SNP- and three SNP-haplotypes showed significant associations; the associations of haplotypes involving rs2249057 withstand multiple testing correction. No associations were observed for DBZ with schizophrenia or with bipolar disorder; further, there was no significant difference between the DBZ mRNA levels of control, schizophrenia and bipolar postmortem brains. We suggest a possible role of PCNT2 in the pathogenesis of schizophrenia. Abnormalities of PCNT2, the centrosomal protein essential for microtubule organization, may be suggested to lead to neurodevelopmental abnormalities.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 03/2009; 150B(7):967-76. · 3.70 Impact Factor
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Kunihiko Tani,
Masaomi Iyo,
Hideo Matsumoto, Masayoshi Kawai,
Katsuaki Suzuki,
Yasuhide Iwata,
Taketoshi Won,
Toshio Tsukamoto,
Yoshimoto Sekine,
Masatsuna Sakanoue,
Kenji Hashimoto,
Yutaka Ohashi,
Nori Takei,
Norio Mori
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ABSTRACT: We destroyed dentate granule cells unilaterally or bilaterally by means of intrahippocampal injection of colchicine in rats. Subsequently, we observed behavioural changes following the intraperitoneal injection of 2 mg kg−1 methamphetamine or saline, in addition to quantitatively assessing Fos protein expression in several brain regions, including the medial prefrontal cortex, cingulate cortex, piriform cortex, dorsal striatum, and nucleus accumbens.Bilaterally lesioned animals, when administered saline, showed a marked increase in locomotor activity compared with those of non-lesioned animals. With respect to the methamphetamine response, bilateral destruction resulted in a marked enhancement of locomotor activity, while the unilateral destruction led to a marked increase in rotation predominantly contralateral to the lesioned side, with no identifiable change in locomotor activity.Bilaterally lesioned animals, when administered saline and having undergone an immunohistological examination, showed a marked increase in Fos expression in both sides of the nucleus accumbens. Bilaterally lesioned animals administered methamphetamine showed a marked increase in Fos expression in the right and left sides of all regions tested. Unilaterally lesioned animals administered methamphetamine showed a significant and bilateral enhancement in Fos expression in the medial prefrontal and cingulate cortices, and a marked and unilateral (ipsilateral to the lesioned side) enhancement of Fos protein in the piriform cortex, dorsal striatum, and nucleus accumbens.The present findings suggest that dentate granule cells regulate methamphetamine-associated behavioural changes through the function of widespread areas of the brain, mostly the nucleus accumbens.British Journal of Pharmacology (2001) 134, 1411–1418; doi:10.1038/sj.bjp.0704370
British Journal of Pharmacology 01/2009; 134(7):1411 - 1418. · 4.41 Impact Factor
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Kazuhiko Nakamura,
Ayyappan Anitha,
Kazuo Yamada,
Masatsugu Tsujii,
Yoshimi Iwayama,
Eiji Hattori,
Tomoko Toyota,
Shiro Suda,
Noriyoshi Takei,
Yasuhide Iwata,
Katsuaki Suzuki,
Hideo Matsuzaki, Masayoshi Kawai,
Yoshimoto Sekine,
Kenji J. Tsuchiya,
Gen-ichi Sugihara,
Yasuomi Ouchi,
Toshiro Sugiyama,
Takeo Yoshikawa,
Norio Mori
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ABSTRACT: Autism is a pervasive developmental disorder diagnosed in early childhood. Abnormalities of serotonergic neurotransmission have been reported in autism. Serotonin transporter (5-HTT), which modulates serotonin levels, is a major therapeutic target in autism. Therefore, factors that regulate 5-HTT expression might be implicated in autism. One candidate 5-HTT-regulatory protein is the presynaptic protein, syntaxin 1A (STX1A). We examined the association of STX1A with autism in a trio association study using DNA samples from 249 AGRE trios with autistic probands. Only male probands were selected, since autism is more prevalent among males. The probands of 102 trios had IQ>70, and were considered as high functioning autism (HFA). In transmission disequilibrium test (TDT) analysis, rs2293485 (p=0.034) and rs4717806 (p=0.033) showed nominal associations with HFA; modest haplotype association was also observed. The SNPs that showed associations were related to early developmental abnormalities (ADI-R_D). We further compared STX1A mRNA expression in the lymphocytes of drug-naive HFA patients (n=12) and age- and sex-matched controls (n=13). STX1A expression in the HFA group was significantly higher (p=0.001) than that of controls. Thus, we suggest a possible role of STX1A in the pathogenesis of HFA. During early childhood, there is a period of high brain serotonin synthesis that is disrupted in autistic children; STX1A might influence the serotonergic system during this stage of neurodevelopment, as implied by the association with ADI-R_D.
The International Journal of Neuropsychopharmacology 11/2008; 11(08):1073 - 1084. · 4.58 Impact Factor
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Kenji J Tsuchiya,
Kaori Matsumoto,
Taishi Miyachi,
Masatsugu Tsujii,
Kazuhiko Nakamura,
Shu Takagai, Masayoshi Kawai,
Atsuko Yagi,
Kimie Iwaki,
Shiro Suda,
Genichi Sugihara,
Yasuhide Iwata,
Hideo Matsuzaki,
Yoshimoto Sekine,
Katsuaki Suzuki,
Toshirou Sugiyama,
Norio Mori,
Nori Takei
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ABSTRACT: Previous studies have reported the association between advanced paternal age at birth and the risk of autistic-spectrum disorder in offspring, including offspring with intellectual disability.
To test whether an association between advanced paternal age at birth is found in offspring with high-functioning autistic-spectrum disorder (i.e. offspring without intellectual disability).
A case-control study was conducted in Japan. The participants consisted of individuals with full-scale IQ>or=70, with a DSM-IV autistic disorder or related diagnosis. Unrelated healthy volunteers were recruited as controls. Parental ages were divided into tertiles (i.e. three age classes). Odds ratios and 95% confidence intervals were estimated using logistic regression analyses, with an adjustment for age, gender and birth order.
Eighty-four individuals with autistic-spectrum disorder but without intellectual disability and 208 healthy controls were enrolled. Increased paternal, but not maternal, age was associated with an elevated risk of high-functioning autistic-spectrum disorder. A one-level advance in paternal age class corresponded to a 1.8-fold increase in risk, after adjustment for covariates.
Advanced paternal age is associated with an increased risk for high-functioning autistic-spectrum disorder.
The British journal of psychiatry: the journal of mental science 11/2008; 193(4):316-21. · 6.62 Impact Factor
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Norikazu Ezaki,
Kazuhiko Nakamura,
Yoshimoto Sekine,
Ismail Thanseem,
Ayyappan Anitha,
Yasuhide Iwata, Masayoshi Kawai,
Kiyokazu Takebayashi,
Katsuaki Suzuki,
Nori Takei,
Masaomi Iyo,
Toshiya Inada,
Nakao Iwata,
Mutsuo Harano,
Tokutaro Komiyama,
Mitsuhiko Yamada,
Ichiro Sora,
Hiroshi Ujike,
Norio Mori
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ABSTRACT: Accumulating evidence suggests that genetic factors contribute to the vulnerability to methamphetamine (MAP) abuse and associated psychiatric symptoms. Chronic MAP abuse leads to psychosis, which may be of a transient or a prolonged type. Serotonergic dysfunction has been proposed as one of the contributory factors in the development of MAP psychosis. Our PET studies revealed that the serotonin transporter (5-HTT) density in global brain regions is significantly lower in MAP abusers. In this study, we examined the role of a functional polymorphism in the 5' flanking region of the 5-HTT gene (5-HTTLPR) in the development of MAP psychosis in a Japanese population. We analyzed DNA samples from 166 MAP patients (95 with transient and 71 with prolonged psychosis) and 197 age-, sex-, and geographic-origin-matched healthy controls. Patients were also subdivided according to the presence (n= 119) or absence (n= 148) of spontaneous relapse. We observed significant genotypic association of the 5-HTTLPR polymorphism with MAP psychosis (P= 0.022), particularly in patients who show prolonged psychosis. The frequency of the S allele in patients with prolonged psychosis was significantly higher than that of the controls (P= 0.045); it was further higher in patients with prolonged psychosis with spontaneous relapse (P= 0.004). 5-HTTLPR has been suggested to regulate the transcriptional activity of 5-HTT, with S alleles showing lesser transcriptional efficiency and also lower 5-HT(1A) receptor-binding potential. Prolonged MAP use, combined with the high frequency of 5-HTTLPR S-alleles, may lead to reduced 5-HTT levels and 5-HT(1A) receptor-binding potential in the brain, resulting in the dysfunction of the serotonergic system. Thus, we suggest a possible role for the 5-HTTLPR polymorphism in MAP psychosis.
Annals of the New York Academy of Sciences 11/2008; 1139:49-56. · 3.15 Impact Factor
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Yoshimoto Sekine,
Yasuomi Ouchi,
Genichi Sugihara,
Nori Takei,
Etsuji Yoshikawa,
Kazuhiko Nakamura,
Yasuhide Iwata,
Kenji J Tsuchiya,
Shiro Suda,
Katsuaki Suzuki, Masayoshi Kawai,
Kiyokazu Takebayashi,
Shigeyuki Yamamoto,
Hideo Matsuzaki,
Takatoshi Ueki,
Norio Mori,
Mark S Gold,
Jean L Cadet
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ABSTRACT: Methamphetamine is a popular addictive drug whose use is associated with multiple neuropsychiatric adverse events and toxic to the dopaminergic and serotonergic systems of the brain. Methamphetamine-induced neuropathology is associated with increased expression of microglial cells that are thought to participate in either pro-toxic or protective mechanisms in the brain. Although reactive microgliosis has been observed in animal models of methamphetamine neurotoxicity, no study has reported on the status of microglial activation in human methamphetamine abusers. The present study reports on 12 abstinent methamphetamine abusers and 12 age-, gender-, and education-matched control subjects who underwent positron emission tomography using a radiotracer for activated microglia, [(11)C](R)-(1-[2-chlorophenyl]-N-methyl-N-[1-methylpropyl]-3-isoquinoline carboxamide) ([(11)C](R)-PK11195). Compartment analysis was used to estimate quantitative levels of binding potentials of [(11)C](R)-PK11195 in brain regions with dopaminergic and/or serotonergic innervation. The mean levels of [(11)C](R)-PK11195 binding were higher in methamphetamine abusers than those in control subjects in all brain regions (>250% higher; p < 0.01 for all). In addition, the binding levels in the midbrain, striatum, thalamus, and orbitofrontal and insular cortices (p < 0.05) correlated inversely with the duration of methamphetamine abstinence. These results suggest that chronic self-administration of methamphetamine can cause reactive microgliosis in the brains of human methamphetamine abusers, a level of activation that appears to subside over longer periods of abstinence.
Journal of Neuroscience 06/2008; 28(22):5756-61. · 7.11 Impact Factor
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Ayyappan Anitha,
Kazuhiko Nakamura,
Kazuo Yamada,
Yoshimi Iwayama,
Tomoko Toyota,
Nori Takei,
Yasuhide Iwata,
Katsuaki Suzuki,
Yoshimoto Sekine,
Hideo Matsuzaki, [......],
Taiichi Katayama,
Shinsuke Matsuzaki,
Kousuke Baba,
Akiko Honda,
Tsuyoshi Hattori,
Shoko Shimizu,
Natsuko Kumamoto,
Masaya Tohyama,
Takeo Yoshikawa,
Norio Mori
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ABSTRACT: DISC1 has been suggested as a causative gene for psychoses in a large Scottish kindred. PCNT2 has recently been identified as an interacting partner of DISC1. In this study, we investigated the role of PCNT2 in bipolar disorder, by gene expression analysis and genetic association study.
By TaqMan real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), we examined the messenger RNA (mRNA) levels of PCNT2 in the postmortem prefrontal cortex of bipolar disorder (n = 34), schizophrenia (n = 31), and control subjects (n = 32), obtained from Stanley Array Collection. We also compared the mRNA levels of PCNT2 in the peripheral blood lymphocytes of bipolar disorder (n = 21), schizophrenia (n = 21), depression (n = 33), and control subjects (n = 57). For the association study, 23 single nucleotide polymorphisms (SNPs) were analyzed in 285 bipolar disorder patients and 287 age-and gender-matched control subjects, all of Japanese origin. The genotypes were determined by TaqMan assay.
Significantly higher expression of PCNT2 was observed in the brain samples of bipolar group, compared with the control (p = .001) and schizophrenia (p = .018) groups. In the peripheral blood lymphocytes also, a significantly higher expression of PCNT2 was observed in the bipolar group, compared with the control subjects (p = .043). However, none of the SNPs analyzed in our study showed a significant association with bipolar disorder; a weak tendency toward association was observed for two intronic SNPs.
Our findings suggest that elevated levels of PCNT2 might be implicated in the pathophysiology of bipolar disorder.
Biological psychiatry 05/2008; 63(7):678-85. · 8.93 Impact Factor
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A Anitha,
Kazuhiko Nakamura,
Kazuo Yamada,
Shiro Suda,
Ismail Thanseem,
Masatsugu Tsujii,
Yoshimi Iwayama,
Eiji Hattori,
Tomoko Toyota,
Taishi Miyachi, [......],
Yoshimoto Sekine,
Kenji Tsuchiya,
Gen-Ichi Sugihara,
Yasuomi Ouchi,
Toshiro Sugiyama,
Keita Koizumi,
Haruhiro Higashida,
Nori Takei,
Takeo Yoshikawa,
Norio Mori
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ABSTRACT: Autism is a pervasive developmental disorder diagnosed in early childhood. Abnormalities of serotonergic neurotransmission have been reported in autism. Serotonin transporter (SERT) modulates serotonin levels, and is a major therapeutic target in autism. Factors that regulate SERT expression might be implicated in the pathophysiology of autism. One candidate SERT regulatory protein is the roundabout axon guidance molecule, ROBO. SerT expression in Drosophila is regulated by robo; it plays a vital role in mammalian neurodevelopment also. Here, we examined the associations of ROBO3 and ROBO4 with autism, in a trio association study using DNA from 252 families recruited to AGRE. Four SNPs of ROBO3 (rs3923890, P = 0.023; rs7925879, P = 0.017; rs4606490, P = 0.033; and rs3802905, P = 0.049) and a single SNP of ROBO4 (rs6590109, P = 0.009) showed associations with autism; the A/A genotype of rs3923890 showed lower ADI-R_A scores, which reflect social interaction. Significant haplotype associations were also observed for ROBO3 and ROBO4. We further compared the mRNA expressions of ROBO1, ROBO2, ROBO3, and ROBO4 in the lymphocytes of 19 drug-naïve autistic patients and 20 age- and sex-matched controls. Expressions of ROBO1 (P = 0.018) and ROBO2 (P = 0.023) were significantly reduced in the autistic group; the possibility of using the altered expressions of ROBO as peripheral markers for autism, may be explored. In conclusion, we suggest a possible role of ROBO in the pathogenesis of autism. Abnormalities of ROBO may lead to autism either by interfering with serotonergic system, or by disrupting neurodevelopment. To the best of our knowledge, this is the first report relating ROBO with autism.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 03/2008; 147B(7):1019-27. · 3.70 Impact Factor
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Katsuaki Suzuki,
Kazuhiko Nakamura,
Yasuhide Iwata,
Yoshimoto Sekine, Masayoshi Kawai,
Genichi Sugihara,
Kenji J Tsuchiya,
Shiro Suda,
Hideo Matsuzaki,
Nori Takei,
Kenji Hashimoto,
Norio Mori
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ABSTRACT: Reelin, a secretory protease that plays major roles in neurodevelopment and synaptic plasticity, may also play a role in the pathogenesis of schizophrenia. The present study was undertaken to examine whether the expression of two receptors for reelin, very low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor type 2 (ApoER2), were abnormal in peripheral blood lymphocytes of schizophrenic patients. In this study, we measured the mRNA levels of VLDLR and ApoER2 in blood lymphocytes from patients with schizophrenia (drug-naive patients (n=20) and medicated patients (n=20)) and age-and gender-matched healthy controls (n=40) using quantitative real-time RT-PCR. Furthermore, we examined the correlation between mRNA levels and clinical variables in patients. Levels of VLDLR mRNA in drug-naive, unmedicated patients with schizophrenia were significantly lower than those of controls. In contrast, levels of ApoER2 mRNA in drug-naive patients did not differ from those of controls, although the levels of ApoER2 mRNA in medicated patients were significantly lower than those of controls. Interestingly, levels of VLDLR mRNA in drug-naive patients showed significant increases with respect to baseline after six months of antipsychotic treatment, whereas levels of ApoER2 mRNA were significantly lower than baseline after six months of treatment. In all patients, there was a negative correlation between VLDLR mRNA levels and the severity of clinical symptoms. Our findings suggest that peripheral VLDLR mRNA levels may serve as a reliable peripheral biological marker of schizophrenia, and that the reelin-VLDLR/ApoER2 signaling pathway plays a role in the pathophysiology of schizophrenia.
Schizophrenia Research 02/2008; 98(1-3):148-56. · 4.75 Impact Factor
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Kenji J Tsuchiya,
Kenji Hashimoto,
Yasuhide Iwata,
Masatsugu Tsujii,
Yoshimoto Sekine,
Genichi Sugihara,
Hideo Matsuzaki,
Shiro Suda, Masayoshi Kawai,
Kazuhiko Nakamura,
Yoshio Minabe,
Atsuko Yagi,
Masaomi Iyo,
Nori Takei,
Norio Mori
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ABSTRACT: Accumulating evidence suggests that the immune system plays a role in the pathophysiology of autism, and that the adhesion molecules play an important role in the process of inflammation. This study was undertaken to determine whether serum levels of the adhesion molecules in subjects with high-functioning autism are altered as compared with those of normal controls.
Seventeen male subjects with high-functioning autism and 22 male age-matched unrelated healthy control subjects were enrolled. Serum levels of the soluble forms of platelet-endothelial adhesion molecule (PECAM-1), intracellular adhesion molecule (ICAM-1), and vascular cell adhesion molecule (VCAM-1) were measured.
Levels of PECAM-1, but not ICAM-1, in the subjects with autism were significantly lower than those of control subjects. VCAM-1 showed a weak trend for a lowered level. There was a negative correlation between serum levels of PECAM-1 and head circumference at birth in the autistic subjects.
These results suggest that PECAM-1 plays a role in the pathophysiology of high-functioning autism.
Biological Psychiatry 12/2007; 62(9):1056-8. · 8.28 Impact Factor
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Takao Toyoda,
Kazuhiko Nakamura,
Kazuo Yamada,
Ismail Thanseem,
Ayyappan Anitha,
Shiro Suda,
Masatsugu Tsujii,
Yoshimi Iwayama,
Eiji Hattori,
Tomoko Toyota, [......],
Hideo Matsuzaki, Masayoshi Kawai,
Yoshimoto Sekine,
Kenji Tsuchiya,
Gen-ichi Sugihara,
Yasuomi Ouchi,
Toshiro Sugiyama,
Nori Takei,
Takeo Yoshikawa,
Norio Mori
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ABSTRACT: Autism is a pervasive neurodevelopmental disorder diagnosed in early childhood. Growth factors have been found to play a key role in the cellular differentiation and proliferation of the central and peripheral nervous systems. Epidermal growth factor (EGF) is detected in several regions of the developing and adult brain, where, it enhances the differentiation, maturation, and survival of a variety of neurons. Transforming growth factor-beta (TGFbeta) isoforms play an important role in neuronal survival, and the hepatocyte growth factor (HGF) has been shown to exhibit neurotrophic activity. We examined the association of EGF, TGFbeta1, and HGF genes with autism, in a trio association study, using DNA samples from families recruited to the Autism Genetic Resource Exchange; 252 trios with a male offspring scored for autism were selected for the study. Transmission disequilibrium test revealed significant haplotypic association of EGF with autism. No significant SNP or haplotypic associations were observed for TGFbeta1 or HGF. Given the role of EGF in brain and neuronal development, we suggest a possible role of EGF in the pathogenesis of autism.
Biochemical and Biophysical Research Communications 10/2007; 360(4):715-20. · 2.48 Impact Factor
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Katsuaki Suzuki,
Kenji Hashimoto,
Yasuhide Iwata,
Kazuhiko Nakamura,
Masatsugu Tsujii,
Kenji J Tsuchiya,
Yoshimoto Sekine,
Shiro Suda,
Genichi Sugihara,
Hideo Matsuzaki,
Toshiro Sugiyama, Masayoshi Kawai,
Yoshio Minabe,
Nori Takei,
Norio Mori
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ABSTRACT: The neurobiological basis for autism remains poorly understood. Given the role of growth factors in brain development, we hypothesized that epidermal growth factor (EGF) may play a role in the pathophysiology of autism. In this study, we examined whether serum levels of EGF are altered in adult subjects with high-functioning autism.
We measured serum levels of EGF in the 17 male subjects with high-functioning autism and 18 age-matched healthy male subjects.
The serum levels of EGF in the subjects with high-functioning autism (72.4 +/- 102.8 pg/mL [mean +/- SD]) were significantly lower (Mann-Whitney U = 22.0, p < .001) than those of normal control subjects (322.3 +/- 122.0 pg/mL [mean +/- SD]). However, there were no correlations between serum EGF levels and clinical variables in the subjects with autism.
This study suggests that decreased levels of EGF might be implicated in the pathophysiology of high-functioning autism.
Biological Psychiatry 08/2007; 62(3):267-9. · 8.28 Impact Factor
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Katsuhiko Nishimura,
Kazuhiko Nakamura,
A Anitha,
Kazuo Yamada,
Masatsugu Tsujii,
Yoshimi Iwayama,
Eiji Hattori,
Tomoko Toyota,
Nori Takei,
Taishi Miyachi, [......],
Hideo Matsuzaki, Masayoshi Kawai,
Yoshimoto Sekine,
Kenji Tsuchiya,
Gen-ichi Sugihara,
Shiro Suda,
Yasuomi Ouchi,
Toshiro Sugiyama,
Takeo Yoshikawa,
Norio Mori
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ABSTRACT: Autism is a severe neurodevelopmental disorder defined by social and communication deficits and ritualistic-repetitive behaviors that are detectable in early childhood. Brain-derived neurotrophic factor (BDNF) plays a critical role in the pathogenesis of autism. In this study, we examined the SNP- and haplotypic-association of BDNF with autism in a trios-based association study (the Autism Genetic Resource Exchange). We also examined the expression of BDNF mRNA in the peripheral blood lymphocytes of drug-naïve autism patients and control subjects. In the TDT of autism trios, the SNP haplotype combinations showed significant associations in the autism group. BDNF expression in the drug-naïve autistic group was found to be significantly higher than in the control group. We suggest that BDNF has a possible role in the pathogenesis of autism through its neurotrophic effects on the serotonergic system.
Biochemical and Biophysical Research Communications 05/2007; 356(1):200-6. · 2.48 Impact Factor
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Genichi Sugihara,
Kenji Hashimoto,
Yasuhide Iwata,
Kazuhiko Nakamura,
Masatsugu Tsujii,
Kenji J Tsuchiya,
Yoshimoto Sekine,
Katsuaki Suzuki,
Shiro Suda,
Hideo Matsuzaki, Masayoshi Kawai,
Yoshio Minabe,
Atsuko Yagi,
Nori Takei,
Toshiro Sugiyama,
Norio Mori
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ABSTRACT: The mechanisms underlying the pathophysiology of autism are currently unknown. Given the role of hepatocyte growth factor (HGF) in brain development, we hypothesized that HGF plays a role in the pathophysiology of autism. In this study, we studied whether serum HGF levels are altered in subjects with high-functioning autism.
Using an enzyme-linked immunosorbent assay (ELISA), we measured serum levels of HGF in 17 male adults with high-functioning autism and age-matched 18 male healthy subjects.
The serum levels (503.5+/-160.5 pg/mL (mean+/-SD)) of HGF in the subjects with high-functioning autism were significantly (Mann-Whitney U=34.0, p<0.001) lower than those (817.6+/-232.4 pg/mL (mean+/-SD)) of control subjects. However, there were no correlations between serum HGF levels and clinical variables in the patients.
This study suggests that reduced HGF levels may play a role in the pathophysiology of high-functioning autism.
Progress in Neuro-Psychopharmacology and Biological Psychiatry 03/2007; 31(2):412-5. · 3.25 Impact Factor
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Yasuhide Iwata,
Katsuaki Suzuki,
Kazuhiko Nakamura,
Hideo Matsuzaki,
Yoshimoto Sekine,
Kenji J Tsuchiya,
Genichi Sugihara, Masayoshi Kawai,
Yoshio Minabe,
Nori Takei,
Norio Mori
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ABSTRACT: Numerous studies have linked schizophrenia with altered immune function. The selectin family of adhesion molecules plays a prominent role in immune/inflammatory responses. To further study the immunological processes in the pathophysiology of schizophrenia, we determined the serum levels of selectins in patients with schizophrenia. For specificity, we also investigated selectin levels in patients with major depression.
We studied 23 unmedicated patients with schizophrenia, 17 unmedicated patients with major depression, and 36 healthy subjects. The serum levels of three types of soluble-form selectin (sE-, sL- and sP-selectin) were determined by enzyme-linked immunosorbent assay (ELISA).
Serum sL-selectin levels were significantly higher in patients with schizophrenia than in either control subjects (p=0.005) or patients with major depression (p=0.02). No significant difference was found with regard to the level of either serum sE-selectin or sP-selectin.
Elevated sL-selectin levels in patients with schizophrenia may represent immune system dysfunction and may be involved in the pathogenesis of the illness.
Schizophrenia Research 02/2007; 89(1-3):154-60. · 4.75 Impact Factor
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Kyoko Okada,
Kenji Hashimoto,
Yasuhide Iwata,
Kazuhiko Nakamura,
Masatsugu Tsujii,
Kenji J Tsuchiya,
Yoshimoto Sekine,
Shiro Suda,
Katsuaki Suzuki,
Gen-ichi Sugihara,
Hideo Matsuzaki,
Toshiro Sugiyama, Masayoshi Kawai,
Yoshio Minabe,
Nori Takei,
Norio Mori
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ABSTRACT: The neurobiological basis for autism remains poorly understood. Given the key role of transforming growth factor-beta1 (TGF-beta1) in brain development, we hypothesized that TGF-beta1 plays a role in the pathophysiology of autism. In this study, we studied whether serum levels of TGF-beta1 are altered in patients with autism.
We measured serum levels of TGF-beta1 in 19 male adult patients with autism and 21 age-matched male healthy subjects using enzyme-linked immunosorbent assay (ELISA).
The serum levels (7.34+/-5.21 ng/mL (mean+/-S.D.)) of TGF-beta1 in the patients with autism were significantly (z=-5.106, p<0.001) lower than those (14.48+/-1.64 ng/mL (mean+/-S.D.)) of normal controls. However, there were no marked or significant correlations between serum TGF-beta1 levels and other clinical variables, including Autism Diagnostic Interview-Revised (ADI-R) scores, Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), aggression, Theory of Mind, and Intellectual Quotient (IQ) in patients.
These findings suggest that decreased levels of TGF-beta1 may be implicated in the pathophysiology of autism.
Progress in Neuro-Psychopharmacology and Biological Psychiatry 01/2007; 31(1):187-90. · 3.25 Impact Factor
