Publications by authors named "Masanori Ishikawa"

34 Publications

[Herpes simplex encephalitis presenting as a stroke-like episode following a migraine attack: a case report].

Rinsho Shinkeigaku 2022 Jul 24;62(7):567-570. Epub 2022 Jun 24.

Department of Neurology, Nagaoka Red Cross Hospital.

A 23-year-old woman, who had been suffering from migraine since primary school age, presented with left arm paralysis three days after one such migraine attack. On admission, brain MRI diffusion-weighted imaging (DWI) demonstrated high-signal-intensity lesions in the white matter of the right fronto-parietal lobe, and no abnormal lesions were evident in the limbic system. Although the patient had a fever of 38.7°C, the CSF cell count was not elevated. On the 4‍ day, the left arm paralysis worsened, with an increase in body temperature to 39.8°C. Brain MRI revealed that the white matter lesions had spread to the right postcentral gyrus and the bilateral insular cortex. Also, MR angiography demonstrated no spasms or dissection of the major vessels. On the 6‍ day, the CSF cell count was elevated to 54/μl and herpes simplex virus DNA was detected. Acyclovir and steroid pulse therapy ameliorated the symptoms. Cervical artery dissection and reversible cerebral vasoconstriction are well known complications of migraine attack. However, herpes simplex encephalitis should also be considered as a differential diagnosis in patients with a high fever of unknown origin.
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http://dx.doi.org/10.5692/clinicalneurol.cn-001745DOI Listing
July 2022

Bipolar disorder in megalencephalic leukoencephalopathy with subcortical cysts: a case report.

BMC Psychiatry 2020 07 3;20(1):349. Epub 2020 Jul 3.

Department of Child Neurology, National Center Hospital of Neurology and Psychiatry, National Center of Neurology and Psychiatry, Tokyo, 187-8551, Japan.

Background: Megalencephalic leukoencephalopathy with subcortical cysts (MLC), or Van der Knaap disease, is a rare spongiform leukodystrophy that is characterized by macrocephaly, progressive motor dysfunction, and mild mental retardation. It is very rare for mental illness such as psychotic disorders, affective disorders and anxiety disorders to occur in MLC.

Case Presentation: A 17-year-old boy was admitted to our hospital after he developed symptoms of depressive state with catatonia after being diagnosed as having MLC with confirmed MLC1 mutation. His catatonic symptoms were improved with administration of olanzapine and sertraline and he was discharged after 4 months. Several months later, he became hypomanic. He was diagnosed with bipolar II disorder. Mood swings were controlled with the administration of carbamazepine.

Conclusions: This case is the first report of bipolar disorder during the clinical course of MLC. This case indicate the possibility that MLC influences the development of bipolar disorder in MLC, however, further studies involving more patients are required to clarify this.
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http://dx.doi.org/10.1186/s12888-020-02750-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333431PMC
July 2020

Angiogenesis in the ischemic core: A potential treatment target?

J Cereb Blood Flow Metab 2019 05 6;39(5):753-769. Epub 2019 Mar 6.

3 Department of Medicine (Division of Hematology), University of Washington, Seattle, WA, USA.

The ischemic penumbra is both a concept in understanding the evolution of cerebral tissue injury outcome of focal ischemia and a potential therapeutic target for ischemic stroke. In this review, we examine the evidence that angiogenesis can contribute to beneficial outcomes following focal ischemia in model systems. Several studies have shown that, following cerebral ischemia, endothelial proliferation and subsequent angiogenesis can be detected beginning four days after cerebral ischemia in the border of the ischemic core, or in the ischemic periphery, in rodent and non-human primate models, although initial signals appear within hours of ischemia onset. Components of the neurovascular unit, its participation in new vessel formation, and the nature of the core and penumbra responses to experimental focal cerebral ischemia, are considered here. The potential co-localization of vascular remodeling and axonal outgrowth following focal cerebral ischemia based on the definition of tissue remodeling and the processes that follow ischemic stroke are also considered. The region of angiogenesis in the ischemic core and its surrounding tissue (ischemic periphery) may be a novel target for treatment. We summarize issues that are relevant to model studies of focal cerebral ischemia looking ahead to potential treatments.
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http://dx.doi.org/10.1177/0271678X19834158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6501515PMC
May 2019

Brain structure differences among male schizophrenic patients with history of serious violent acts: an MRI voxel-based morphometric study.

BMC Psychiatry 2017 03 21;17(1):105. Epub 2017 Mar 21.

Department of Psychiatry, Saitama Medical University, 38 Morohongo Moroyama-machi, Iruma-gun, Saitama, 350-0495, Japan.

Background: The biological underpinnings of serious violent behaviors in patients with schizophrenia remain unclear. The aim of this study was to identify the characteristics of brain morphometry in patients with schizophrenia and a history of serious violent acts, who were being treated under relatively new legislation for offenders with mental illness in Japan where their relevant action should be strongly associated with their mental illness. We also investigated whether morphometric changes would depend on types of serious violent actions or not.

Methods: Thirty-four male patients with schizophrenia who were hospitalized after committing serious violent acts were compared with 23 male outpatients or inpatients with schizophrenia and no history of violent acts. T1-weighted magnetic resonance imaging (MRI) with voxel-based morphometry was used to assess gray matter volume. Additionally, patients with violent acts were divided based on whether their relevant actions were premeditated or not. The regional volumes of these two groups were compared to those of the control patient group.

Results: Patients with schizophrenia and a history of serious violent acts showed significantly smaller regional volumes of the right inferior temporal area expanded to the middle temporal gyrus and the temporal pole, and the right insular area compared to patients without a history of violence. Patients with premeditated violent acts showed significantly smaller regional volumes of the right inferior temporal area, the right insular area, the left planum polare area including the insula, and the bilateral precuneus area including the posterior cingulate gyrus than those without a history of violence, whereas patients with impulsive violent acts showed significantly smaller volumes of only the right inferior temporal area compared to those without a history of violence.

Conclusions: Patients with schizophrenia and a history of serious violent acts showed structural differences in some brain regions compared to those with schizophrenia and no history of violence. Abnormalities in the right inferior temporal area were relatively common but did not depend on whether the violent actions were premeditated or not, and abnormalities in a wider range may be attributed to not only planning the violent action against others but also to maintaining that plan.

Trial Registration: UMIN.ac.jp UMIN000008065 . Registered 2012/05/31.
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http://dx.doi.org/10.1186/s12888-017-1263-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5361832PMC
March 2017

Microglia preconditioned by oxygen-glucose deprivation promote functional recovery in ischemic rats.

Sci Rep 2017 02 14;7:42582. Epub 2017 Feb 14.

Department of Neurology, Brain Research Institute, Niigata University, 1-757 Asahimachi-dori, Chuoku, Niigata, Japan.

Cell-therapies that invoke pleiotropic mechanisms may facilitate functional recovery in stroke patients. We hypothesized that a cell therapy using microglia preconditioned by optimal oxygen-glucose deprivation (OGD) is a therapeutic strategy for ischemic stroke because optimal ischemia induces anti-inflammatory M2 microglia. We first delineated changes in angiogenesis and axonal outgrowth in the ischemic cortex using rats. We found that slight angiogenesis without axonal outgrowth were activated at the border area within the ischemic core from 7 to 14 days after ischemia. Next, we demonstrated that administration of primary microglia preconditioned by 18 hours of OGD at 7 days prompted functional recovery at 28 days after focal cerebral ischemia compared to control therapies by marked secretion of remodelling factors such as vascular endothelial growth factor, matrix metalloproteinase-9, and transforming growth factor-β polarized to M2 microglia in vitro/vivo. In conclusion, intravascular administration of M2 microglia preconditioned by optimal OGD may be a novel therapeutic strategy against ischemic stroke.
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http://dx.doi.org/10.1038/srep42582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5307390PMC
February 2017

A case of slowly progressive anti-Yo-associated paraneoplastic cerebellar degeneration successfully treated with antitumor and immunotherapy.

Rinsho Shinkeigaku 2016 07 30;56(7):477-80. Epub 2016 Jun 30.

Department of Neurology, Niigata University.

We report a case of slowly progressive anti-Yo-associated paraneoplastic cerebellar degeneration (PCD) with breast cancer in a 54-year-old woman. The symptoms of limb and truncal ataxia, and dysarthria gradually progressed during the course of 1 year, and the modified Rankin scale (mRS) score was 2. A mastectomy with sentinel lymph node resection was performed for the breast cancer. No malignant cells were found on histopathological examination of the lymph node. Combination chemotherapy with adriamycin and cyclophosphamide (AC) prevented neurologic deterioration. However, subsequent treatment with trastuzumab and paclitaxel did not prevent progression of the symptoms (mRS score 3). Brain magnetic resonance imaging showed atrophy of the cerebellar hemispheres without brain stem atrophy. Anti-Yo antibody was detected in the serum, which led to a diagnosis of anti-Yo-associated PCD. We resected an enlarged axillary lymph node, which was found on computed tomography. The histopathological analysis of the lymph node revealed foreign body granuloma, which suggested an association with necrotic malignant tissue. Following additional tegafur-uracil therapy and two courses of intravenous immunoglobulin (IVIg), the cerebellar signs and symptoms gradually improved (mRS score 2). The clinical course shows that PCD can present as a slowly progressive cerebellar symptom. We propose an active treatment for anti-Yo-associated PCD consisting of tumor resection, combined chemotherapy, and IVIg.
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http://dx.doi.org/10.5692/clinicalneurol.cn-000872DOI Listing
July 2016

Neurocognitive features in male patients with schizophrenia exhibiting serious violence: a case control study.

Ann Gen Psychiatry 2015 21;14:46. Epub 2015 Dec 21.

Department of Neuropsychiatry, Faculty of Life Sciences, Kumamoto University, Kumamoto, Kumamoto Japan.

Background: The relationship between violence and neurocognitive function in schizophrenia is unclear. We examined the backgrounds and neurocognitive functions of violent and nonviolent patients with schizophrenia to identify factors associated with serious violence.

Methods: Thirty male patients with schizophrenia who were hospitalized after committing serious violent acts were compared with 24 hospitalized male patients with schizophrenia and no history of violence. We evaluated psychiatric symptoms using the Positive and Negative Syndrome Scale (PANSS) and neurocognitive functions using the Brief Assessment of Cognition in Schizophrenia (BACS)-Japanese version.

Results: Repeated-measures analyses of variance on BACS subcomponents z-scores showed that the violent and control groups had different neuropsychological profiles at trend level (p = 0.095). Post hoc analyses of variance indicated that the violent group had significantly better working memory and executive function than the control group. In post hoc ANOVAs also controlling for the effect of the presence of substance abuse on cognitive function, violent or nonviolent group had a significant main effect on executive function but not on working memory.

Conclusions: Patient with violent or non-violent schizophrenia have distinct neuropsychological profiles. These results may help develop improved psychosocial treatments.
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http://dx.doi.org/10.1186/s12991-015-0086-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4687370PMC
December 2015

Neurocognitive features in male patients with schizophrenia exhibiting serious violence: a case control study.

Ann Gen Psychiatry 2015 21;14:46. Epub 2015 Dec 21.

Department of Neuropsychiatry, Faculty of Life Sciences, Kumamoto University, Kumamoto, Kumamoto Japan.

Background: The relationship between violence and neurocognitive function in schizophrenia is unclear. We examined the backgrounds and neurocognitive functions of violent and nonviolent patients with schizophrenia to identify factors associated with serious violence.

Methods: Thirty male patients with schizophrenia who were hospitalized after committing serious violent acts were compared with 24 hospitalized male patients with schizophrenia and no history of violence. We evaluated psychiatric symptoms using the Positive and Negative Syndrome Scale (PANSS) and neurocognitive functions using the Brief Assessment of Cognition in Schizophrenia (BACS)-Japanese version.

Results: Repeated-measures analyses of variance on BACS subcomponents z-scores showed that the violent and control groups had different neuropsychological profiles at trend level (p = 0.095). Post hoc analyses of variance indicated that the violent group had significantly better working memory and executive function than the control group. In post hoc ANOVAs also controlling for the effect of the presence of substance abuse on cognitive function, violent or nonviolent group had a significant main effect on executive function but not on working memory.

Conclusions: Patient with violent or non-violent schizophrenia have distinct neuropsychological profiles. These results may help develop improved psychosocial treatments.
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http://dx.doi.org/10.1186/s12991-015-0086-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4687370PMC
December 2015

Pseudo-continuous arterial spin labeling MRI study of schizophrenic patients.

Schizophr Res 2014 Apr 26;154(1-3):113-8. Epub 2014 Feb 26.

Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1, Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan.

Unlabelled: Arterial spin labeling (ASL) magnetic resonance imaging (MRI) is a novel noninvasive technique that can measure regional cerebral blood flow (rCBF). To our knowledge, few studies have examined rCBF in patients with schizophrenia by ASL-MRI. Here we used pseudo-continuous ASL (pCASL) to examine the structural and functional imaging data in schizophrenic patients, taking the regional cerebral gray matter volume into account. The subjects were 36 patients with schizophrenia and 42 healthy volunteers who underwent 3-tesla MRI, diffusion tensor imaging (DTI), and pCASL. We evaluated the gray matter volume imaging, DTI, and pCASL imaging data in a voxel-by-voxel statistical analysis. The schizophrenia patients showed reduced rCBF in the left prefrontal and bilateral occipital cortices compared to the healthy volunteers. There was a significant reduction of gray matter volume in the left inferior frontal cortex in the schizophrenia patients. With respect to the fractional anisotropy (FA) values in the DTI, there were significant FA reductions in the left superior temporal, left external capsule, and left inferior prefrontal regions in the patients compared to the controls.

Conclusion: Our pCASL study with partial volume effect correction together with volumetry and DTI data demonstrated hypoactivity in the left prefrontal area beyond structural abnormalities in schizophrenia patients. There were also hypofunction areas in bilateral occipital cortices, although structural abnormalities were not apparent.
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http://dx.doi.org/10.1016/j.schres.2014.01.035DOI Listing
April 2014

Immunohistochemical analysis of ubiquilin-1 in the human hippocampus: association with neurofibrillary tangle pathology.

Neuropathology 2014 Feb 21;34(1):11-8. Epub 2013 Jul 21.

Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tokyo, Japan.

This post mortem immunohistochemical study examined the localization and distribution of ubiquilin-1 (UBL), a shuttle protein which interacts with ubiquitin and the proteasome, in the hippocampus from Alzheimer's disease (AD) dementia cases, and age-matched cases without dementia. In Braak stages 0-I-II cases, UBL immunoreactivity was detected in a dense fiber network in the neuropil, and in the cell cytoplasm and nucleoplasm of neurons in Cornu Ammonis (CA) fields and dentate gyrus granular neurons. In Braak stages III-IV and V-VI cases, UBL immunoreactivity was reduced in the neuropil and in the cytoplasm of the majority of CA1 neurons; some CA1 pyramidal neurons and the majority of CA2/3 pyramidal, CA4 multipolar, and dentate granular neurons had markedly increased UBL immunoreactivity in the nucleoplasm. Dual immunofluorescence analysis of UBL and antibody clone AT8 revealed co-localization most frequently in CA1 pyramidal neurons in Braak stage III-IV and V-VI cases. Further processing using the pan-amyloid marker X-34 revealed prominent UBL/X-34 dual labeling of extracellular NFT confined to the CA1/subiculum in Braak stage V-VI cases. Our results demonstrate that in AD hippocampus, early NFT changes are associated with neuronal up-regulation of UBL in nucleoplasm, or its translocation from the cytoplasm to the nucleus. The perseverance of UBL changes in CA2/3, CA4 and dentate gyrus, generally considered as more resistant to NFT pathology, but not in the CA1, may mark a compensatory, potentially protective response to increased tau phosphorylation in hippocampal neurons; the failure of such a response may contribute to neuronal degeneration in end-stage AD.
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http://dx.doi.org/10.1111/neup.12055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4000263PMC
February 2014

Discrimination between schizophrenia and major depressive disorder by magnetic resonance imaging of the female brain.

J Psychiatr Res 2013 Oct 3;47(10):1383-8. Epub 2013 Jul 3.

Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1, Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan.

Background: Although schizophrenia and major depressive disorder (MDD) differ on a variety of neuroanatomical measures, a diagnostic tool to discriminate these disorders has not yet been established. We tried to identify structural changes of the brain that best discriminate between schizophrenia and MDD on the basis of gray matter volume, ventricle volume, and diffusion tensor imaging (DTI).

Method: The first exploration sample consisted of 25 female patients with schizophrenia and 25 females with MDD. Regional brain volumes and fractional anisotropy (FA) values were entered into a discriminant analysis. The second validation sample consisted of 18 female schizophrenia and 16 female MDD patients.

Results: The stepwise discriminant analysis resulted in correct classification rates of 0.80 in the schizophrenic group and 0.76 in MDD. In the second validation sample, the obtained model yielded correct classification rates of 0.72 in the schizophrenia group and 0.88 in the MDD group.

Conclusion: Our results suggest that schizophrenia and MDD have differential structural changes in the examined brain regions and that the obtained discriminant score may be useful to discriminate the two disorders.
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http://dx.doi.org/10.1016/j.jpsychires.2013.06.010DOI Listing
October 2013

Discrimination of female schizophrenia patients from healthy women using multiple structural brain measures obtained with voxel-based morphometry.

Psychiatry Clin Neurosci 2012 Dec;66(7):611-7

Department of Mental Disorder Research, National Institute of Neuroscience, Japan.

Aim: Although schizophrenia and control subjects differ on a variety of neuroanatomical measures, the specificity and sensitivity of any one measure for differentiating between the two groups are low. To identify the correlative pattern of brain changes that best discriminate schizophrenia patients from healthy subjects, discriminant analysis techniques using voxel-based morphometry were applied.

Methods: The first analysis was conducted to obtain a statistical model that classified 105 female healthy subjects and 38 female schizophrenia patients. First, the differences in gray matter and cerebrospinal fluid volume between the patients and healthy subjects were evaluated using optimized voxel-based morphometry. Then, a discriminant analysis reflecting the results of this evaluation was adopted. The second analysis was performed to prospectively validate the statistical model by successfully classifying a new group that consisted of 23 female healthy subjects and 23 female schizophrenia patients.

Results: The use of these variables resulted in correct classification rates of 0.72 in the control subjects and 0.76 in the schizophrenia patients. In the second validation analysis using these variables, correct classification rates of 0.70 in the control subjects and 0.74 in the schizophrenia patients were achieved.

Conclusion: Schizophrenia patients have structural deviations in multiple brain areas, and a combination of structural brain measures can distinguish between patients and controls.
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http://dx.doi.org/10.1111/j.1440-1819.2012.02397.xDOI Listing
December 2012

Dropped head syndrome in amyotrophic lateral sclerosis.

Amyotroph Lateral Scler Frontotemporal Degener 2013 Apr 3;14(3):232-3. Epub 2012 Oct 3.

Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan.

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http://dx.doi.org/10.3109/17482968.2012.727424DOI Listing
April 2013

Association of plasma IL-6 and soluble IL-6 receptor levels with the Asp358Ala polymorphism of the IL-6 receptor gene in schizophrenic patients.

J Psychiatr Res 2011 Nov 22;45(11):1439-44. Epub 2011 Jun 22.

Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan.

Recent studies indicate a role of excessive interleukin-6 (IL-6) signaling in the pathogenesis of schizophrenia. A previous study reported a significant association of schizophrenia with the IL-6 receptor (IL-6R) gene Asp358Ala polymorphism, which is known to regulate circulating IL-6 and soluble IL-6R (sIL-6R) levels in healthy subjects. To further examine the influence of the polymorphism in schizophrenic patients, we compared the plasma levels of IL-6 and sIL-6R between schizophrenic patients and healthy controls for each genotype of the Asp358Ala polymorphism. Asp358Ala genotyping and plasma IL-6 level measurements were performed in 104 patients with schizophrenia and 112 healthy controls. Of these participants, 53 schizophrenic patients and 49 controls were selected for the measurement of plasma sIL-6R levels. A two-way factorial analysis of covariance was performed with the transformed plasma levels as the dependent variable, diagnosis and genotype as independent variables, and sex and age as covariates. No significant diagnosis × genotype interaction was observed for IL-6 and sIL-6R levels. The Ala allele of Asp358Ala was significantly associated with higher levels of both IL-6 and sIL-6R. IL-6 levels were significantly elevated in schizophrenic patients compared to those in controls, whereas no significant difference in sIL-6R levels was observed between schizophrenic patients and controls. Our findings suggest that the presence of schizophrenia is associated with elevated IL-6 levels, whereas sIL-6R levels are mainly predetermined by the Asp358Ala genotype and are not associated with the disease status. Increased IL-6 levels without alterations in sIL-6R levels may result in excessive IL-6 signaling in schizophrenia.
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http://dx.doi.org/10.1016/j.jpsychires.2011.06.003DOI Listing
November 2011

Criterion and construct validity of the CogState Schizophrenia Battery in Japanese patients with schizophrenia.

PLoS One 2011 26;6(5):e20469. Epub 2011 May 26.

Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.

Background: The CogState Schizophrenia Battery (CSB), a computerized cognitive battery, covers all the same cognitive domains as the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery but is briefer to conduct. The aim of the present study was to evaluate the criterion and construct validity of the Japanese language version of the CSB (CSB-J) in Japanese patients with schizophrenia.

Methodology/principal Findings: Forty Japanese patients with schizophrenia and 40 Japanese healthy controls with matching age, gender, and premorbid intelligence quotient were enrolled. The CSB-J and the Brief Assessment of Cognition in Schizophrenia, Japanese-language version (BACS-J) were performed once. The structure of the CSB-J was also evaluated by a factor analysis. Similar to the BACS-J, the CSB-J was sensitive to cognitive impairment in Japanese patients with schizophrenia. Furthermore, there was a significant positive correlation between the CSB-J composite score and the BACS-J composite score. A factor analysis showed a three-factor model consisting of memory, speed, and social cognition factors.

Conclusions/significance: This study suggests that the CSB-J is a useful and rapid automatically administered computerized battery for assessing broad cognitive domains in Japanese patients with schizophrenia.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0020469PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3102733PMC
September 2011

An immunohistochemical study of the serotonin 1A receptor in the hippocampus of subjects with Alzheimer's disease.

Neuropathology 2011 Oct 27;31(5):503-9. Epub 2011 Jan 27.

Department of Psychiatry, Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan.

Alzheimer's disease (AD) is associated with neuronal degeneration, synaptic loss and deficits in multiple neurotransmitter systems. Alterations in the serotonin 1A (5-HT1A) receptor can contribute to impaired cognitive function in AD, and both in vitro binding and Positron emission tomography (PET) imaging studies have demonstrated that 5-HT1A receptors in the hippocampus/medial temporal cortex are affected early in AD. This neuropathological study examined the localization and immunoreaction intensity of 5-HT1A receptor protein in AD hippocampus with the goal to determine whether neuronal receptor levels are influenced by the severity of NFT severity defined by Braaks' pathological staging and to provide immunohistochemical confirmation of the binding assays and PET imaging studies. Subjects included AD patients and non-AD controls (NC) stratified into three Braaks' stages (Braak 0-II, NC; Braak III/IV and V/VI, AD). In the Braak 0-II group, 5-HT1A-immunoreactivity (ir) was prominent in the neuropil of the CA1 and subiculum, moderate in the dentate gyrus molecular layer (DGml), and low in the CA3 and CA4. No changes in 5-HT1A-ir were observed in the hippocampus of AD subjects in the Braak III/IV group. Hippocampal 5-HT1A-ir intensity was markedly decreased in the CA1 region in 6/11 (54.5%) subjects in the Braak V/VI group. Across all three groups combined, there was a statistically significant association between reduced 5HT1A-ir and neuronal loss in the CA1, but not in the CA3. The present data demonstrate that hippocampal 5-HT1A receptors are mainly preserved until the end-stage of NFT progression in AD. Thus, the utility of PET imaging using a 5-HT1A-specific radiolabeled probe as a marker of hippocampal neuronal loss may be limited to the CA1 field in advanced stage AD cases.
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http://dx.doi.org/10.1111/j.1440-1789.2010.01193.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3112246PMC
October 2011

Possible association of the semaphorin 3D gene (SEMA3D) with schizophrenia.

J Psychiatr Res 2011 Jan 1;45(1):47-53. Epub 2010 Jun 1.

Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo, Japan.

Semaphorins are ligands of plexins, and the plexin-semaphorin signaling system is widely involved in many neuronal events including axon guidance, cell migration, axon pruning, and synaptic plasticity. The plexin A2 gene (PLXNA2) has been reported to be associated with schizophrenia. This finding prompted us to examine the possible association between the semaphorin 3D gene (SEMA3D) and schizophrenia in a Japanese population. We genotyped 9 tagging single nucleotide polymorphisms (SNPs) of SEMA3D including a non-synonymous variation, Lys701Gln (rs7800072), in a sample of 506 patients with schizophrenia and 941 healthy control subjects. The Gln701 allele showed a significant protective effect against the development of schizophrenia (p = 0.0069, odds ratio = 0.76, 95% confidence interval 0.63 to 0.93). Furthermore, the haplotype-based analyses revealed a significant association. The four-marker analysis (rs2190208-rs1029564-rs17159614-rs12176601), in particular, not including the Lys701Gln, revealed a highly significant association (p = 0.00001, global permutation), suggesting that there may be other functional polymorphisms within SEMA3D. Our findings provide strong evidence that SEMA3D confers susceptibility to schizophrenia, which could contribute to the neurodevelopmental impairments in the disorder.
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http://dx.doi.org/10.1016/j.jpsychires.2010.05.004DOI Listing
January 2011

An immunohistochemical study of GABA A receptor gamma subunits in Alzheimer's disease hippocampus: relationship to neurofibrillary tangle progression.

Neuropathology 2009 Jun 19;29(3):263-9. Epub 2008 Nov 19.

Department of Psychiatry, Ishizaki Hosipital, Ibaraki-machi, Japan.

Immunohistochemical characterization of the distribution of GABA(A) receptor subunits gamma1/3 and 2 in the hippocampus relative to neurofibrillary tangle (NFT) pathology staging was performed in cognitively normal subjects (Braak stage I/II, n = 4) and two groups of Alzheimer's disease (AD) patients (Braak stage III/IV, n = 4; Braak stage V/VI, n = 8). In both Braak groups of AD patients, neuronal gamma1/3 and gamma2 immunoreactivity was preserved in all hippocampal subfields. However, compared to normal controls neuronal gamma1/3 immunoreactivity was more intense in several end-stage AD subjects. Despite increased NFT pathology in the Braak V/VI AD group, GABA(A)gamma1/3 and gamma2 immunoreactivity did not co-localize with markers of NFT. These results suggest that upregulating or preserving GABA(A)gamma1/3 and gamma2 receptors may protect neurons against neurofibrillary pathology in AD.
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http://dx.doi.org/10.1111/j.1440-1789.2008.00978.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3078755PMC
June 2009

[DARPP-32 in the patients with endogenous psychosis].

Brain Nerve 2007 Nov;59(11):1257-63

Tsuchiura Kousei Hospital, 3969 Higashiwakamatsu-cho, Tsuchiura, Ibaraki 300-0064, Japan.

Dopamine- and cyclic AMP-regulated phosphoprotein with a relative molecular weight of 32 kDa (DARPP-32) plays an important role in integrating information of about several neurotransmitters arriving at dopaminoceptive neurons. DARPP-32 is phosphorylated by dopamine D1 receptor at threonine 34 and converted to an inhibitor of protein phosphatase I. It facilitates the phosphorylation of several neurotransmitter receptors, including N-methyl-D-aspartic acid (NMDA)- and alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA)-type glutamate receptors and gamma-aminobutyric acid (GABA)A receptors. In contrast, D2 receptor stimulation induces dephosphorylation of DARPP-32, which results in dephosphorylation of the glutamate and GABAA receptors. Thus, phosphorylation and dephosphorylation of DARPP-32 regulates the functions of neurotransmitter systems. Recent studies from our laboratory and elsewhere have demonstrated that the amount of DARPP-32 in the dorsolateral prefrontal cortex (DLPFC) of subjects with schizophrenia is lower than that in the DLPFC of control subjects. Thus, it is plausible that DARPP-32 is associated with the concurrent alterations in dopamine, glutamate, and GABA neurotransmitter systems in subjects with schizophrenia. We have also found reduced levels of DARPP-32 in the DLPFC of subjects with bipolar disorder. Thus, it is important to elucidate the role of DARPP-32 in the pathophysiology of schizophrenia and bipolar disorder.
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November 2007

Immunohistochemical and immunoblot analysis of Dopamine and cyclic AMP-regulated phosphoprotein, relative molecular mass 32,000 (DARPP-32) in the prefrontal cortex of subjects with schizophrenia and bipolar disorder.

Prog Neuropsychopharmacol Biol Psychiatry 2007 Aug 24;31(6):1177-81. Epub 2007 Apr 24.

Department of Psychiatry, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba City, Ibaraki 305-8575, Japan.

Dopamine and cyclic adenosine 3':5'-monophosphate (AMP)-regulated phosphoprotein, relative molecular mass 32,000 (DARPP-32), plays an important role in modulating the functions of various neurotransmitter systems. To explore the alterations in DARPP-32 in subjects with schizophrenia and bipolar disorder, we employed immunohistochemical and Western blotting techniques and examined the distribution and expression of DARPP-32 in the postmortem dorsolateral prefrontal cortex (DLPFC) from 12 subjects with schizophrenia, 10 subjects with bipolar disorder, and 11 control subjects. Immunohistochemical study demonstrated that DARPP-32 immunolabeling in the neuronal soma from subjects with schizophrenia and bipolar disorder was lower than in that from the controls. The results of the immunoblot analysis were consistent with those of the immunohistochemistry, and the amount of DARPP-32 in subjects with schizophrenia and bipolar disorder was found to be lower than that in the control subjects. The present study suggests that DARPP-32 decreases in the DLPFC of patients with schizophrenia and bipolar disorder, and further suggests that this decrease is associated with dysfunction of dopaminoceptive neurons in the DLPFC of patients affected by these two mental disorders.
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http://dx.doi.org/10.1016/j.pnpbp.2007.04.013DOI Listing
August 2007

GABA(A) receptor gamma subunits in the hippocampus of the rat after perforant pathway lesion.

Neurosci Lett 2006 Feb 2;394(2):88-91. Epub 2005 Nov 2.

Department of Psychiatry, Institute of Clinical Medicine, University of Tsukuba, Tsukuba City, Ibaraki, Japan.

Immunohistochemical and Western blotting techniques were employed to examine the alterations in immunostaining of the gamma-amino butyric acid (GABA) receptor subunits gamma 1/3 and 2 within the hippocampus of the rat brain at 1, 3, 7, 14, and 30 days after a unilateral perforant pathway lesion. At 1, 3, and 7 days post-lesion, we observed a remarkable decrease in gamma 1/3 neuropil staining in the deafferented zone (i.e., the outer molecular layer of the dentate gyrus ipsilateral to the lesion), although at 3 and 7 days post-lesion, staining intensity was considerably recovered. At 14 days post-lesion, the gamma 1/3 immunostaining was indistinguishable from that of controls and it appeared yet more robust at 30 days post-lesion. We also observed a slight decrease in gamma 2 neuropil staining until 7 days post-lesion, and an increase in gamma 2 staining at 30 days post-lesion. Western blot analysis demonstrated data that was relatively consistent with our immunohistochemical observations, although gamma 3 was hardly detectable. Our study suggests that gamma subunits of the GABA(A) receptor in the dentate gyrus display a plastic response to the deafferentation of the perforant pathway.
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http://dx.doi.org/10.1016/j.neulet.2005.10.015DOI Listing
February 2006

Immunohistochemical study of the hnRNP A2 and B1 in the hippocampal formations of brains with Alzheimer's disease.

Neurosci Lett 2005 Sep;386(2):111-5

Department of Psychiatry, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba City, Ibaraki 305-8575, Japan.

To elucidate the post-transcriptional regulation in the subjects with Alzheimer's disease (AD), we employed immunohistochemical techniques and examined the expression of the heterogeneous nuclear ribonucleoprotein (hnRNP) A2 and B1 in the hippocampus with neurofibrillary tangle (NFT) neuropathology. In the mildly affected subjects (Braak stages I and II), the most intense A2 immunoreactivity was observed in the CA3 to CA1 neurons. In the moderately (Braak stages III and IV) and severely affected subjects (Braak stages V and VI), the CA1 region demonstrated a decrease in the number of A2 immunoreactive neurons and in immunoreactivity in the remaining neurons, while within the CA4 to CA2 in the severely affected subjects, the majority of neurons showed increased A2 immunoreactivity. An intense B1 immunoreactivity was observed throughout the CA subfields. In the CA1 subfield of the moderately affected subjects and in the extensive hippocampal regions of the severely affected subjects, a decrease in B1 immunoreactivity was observed. Double-immunolabeling studies demonstrated that tangle-bearing neurons reduced A2 and B1 immunoreactivity. Our study suggests that hnRNP A2 and B1 display different responses in the AD hippocampus, and further suggests that the post-transcriptional regulation is disturbed in neurons of the AD hippocampus.
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http://dx.doi.org/10.1016/j.neulet.2005.05.070DOI Listing
September 2005

Immunohistochemical and immunoblot analysis of gamma-aminobutyric acid B receptor in the prefrontal cortex of subjects with schizophrenia and bipolar disorder.

Neurosci Lett 2005 Aug 26;383(3):272-7. Epub 2005 Apr 26.

Department of Psychiatry, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba City, Ibaraki 305-8575, Japan.

Immunohistochemical and immunoblot techniques were employed to examine the distribution and expression of GABA(B) receptors in the prefrontal cortex of postmortem subjects with schizophrenia and bipolar disorder. GABA(B)R1a/b immunoreactivity was observed in the neuronal soma and dendrites as well as in the neuropil in the control subjects. GABA(B)R1a/b immunolabeling in neurons from the subjects with schizophrenia and bipolar disorder was less intense than in those from the control subjects. In control subjects, the distribution of GABA(B)R2 immunoreactivity was found to be similar to that of GABA(B)R1a/b. GABA(B)R2 immunolabeling in neurons from the bipolar disorder group appeared less intense than that of the normal controls as well as that in schizophrenic groups. Immunoblot analysis demonstrated a significant decrease in GABA(B)R1a levels in schizophrenic subjects, while there was a significant decrease in GABA(B)R1a, GABA(B)R1b, and GABA(B)R2 levels in bipolar subjects compared with the controls. The present study suggests that the GABA(B) receptor is involved in the pathophysiology of schizophrenia and bipolar disorder, and further suggests that the patterns of changes in GABA(B) receptor subtypes are different between these two disorders.
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http://dx.doi.org/10.1016/j.neulet.2005.04.025DOI Listing
August 2005

Changes in hippocampal GABABR1 subunit expression in Alzheimer's patients: association with Braak staging.

Acta Neuropathol 2005 May 10;109(5):467-74. Epub 2005 Mar 10.

Department of Psychiatry, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, 305-8575, Tsukuba city, Ibaraki, Japan.

Alterations in the gamma-aminobutyric acid (GABA) neurotransmitter and receptor systems may contribute to vulnerability of hippocampal pyramidal neurons in Alzheimer's disease (AD). The present study examined the immunohistochemical localization and distribution of GABA(B) receptor R1 protein (GBR1) in the hippocampus of 16 aged subjects with a range of neurofibrillary tangle (NFT) pathology as defined by Braak staging (I-VI). GBR1 immunoreactivity (IR) was localized to the soma and processes of hippocampal pyramidal cells and some non-pyramidal interneurons. In control subjects (Braak I/II), the intensity of neuronal GBR1 immunostaining differed among hippocampal fields, being most prominent in the CA4 and CA3/2 fields, moderate in the CA1 field, and very light in the dentate gyrus. AD cases with moderate NFT pathology (Braak III/IV) were characterized by increased GBR1-IR, particularly in the CA4 and CA3/2 fields. In the CA1 field of the majority of AD cases, the numbers of GBR1-IR neurons were significantly reduced, despite the presence of Nissl-labeled neurons in this region. These data indicate that GBR1 expression changes with the progression of NFT in AD hippocampus. At the onset of hippocampal pathology, increased or stable expression of GBR1 could contribute to neuronal resistance to the disease process. Advanced hippocampal pathology appears to be associated with decreased neuronal GBR1 staining in the CA1 region, which precedes neuronal cell death. Thus, changes in hippocampal GBR1 may reflect alterations in the balance between excitatory and inhibitory neurotransmitter systems, which likely contributes to dysfunction of hippocampal circuitry in AD.
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http://dx.doi.org/10.1007/s00401-005-0985-9DOI Listing
May 2005

Immunohistochemical study of hnRNP B1 in the postmortem temporal cortices of patients with Alzheimer's disease.

Neurosci Res 2004 Dec;50(4):481-4

Department of Psychiatry, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba city, Ibaraki 305-8575, Japan.

In order to examine the post-transcriptional regulations in Alzheimer's disease, we employed immunohistochemical techniques and examined the expression of heterogeneous nuclear ribonucleoprotein (hnRNP) B1 in the inferior temporal cortex of subjects with Alzheimer's disease. In the mild cases, intense B1 immunoreactivity was observed in neurons of layer V, and less intense immunoreactivity was observed in layers II and III. The overall distributions and intensities of B1 immunoreactivity were undistinguishable among mild, moderate, and severe cases. Double-immunolabeling with MC1 and B1 demonstrated that B1 immunoreactivity was preserved in the majority of neurofibrillary tangle (NFT)-bearing neurons. Our study suggests that hnRNP B1-associated post-transcriptional regulations are preserved in the inferior temporal cortex of Alzheimer's disease.
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http://dx.doi.org/10.1016/j.neures.2004.08.013DOI Listing
December 2004

Immunohistochemical and immunoblot study of GABA(A) alpha1 and beta2/3 subunits in the prefrontal cortex of subjects with schizophrenia and bipolar disorder.

Neurosci Res 2004 Sep;50(1):77-84

Department of Psychiatry, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba City, Ibaraki 305-8575, Japan.

A number of investigations have provided a growing body of evidence of the involvement of the gamma-aminobutyric acid (GABA) transmitter system in the pathophysiology of schizophrenia and bipolar disorder. In this study, immunohistochemical and immunoblot techniques were employed in order to examine alterations of the GABA(A) receptor alpha1 and beta2/3 subunits in the prefrontal cortex from postmortem subjects with schizophrenia and bipolar disorder. alpha1 immunoreactivity was observed in the neuropil of the prefrontal cortex and in the neuronal soma in specimens from both groups, as well as from normal controls. alpha1 immunolabeling in the neuronal soma from the schizophrenic group was more intense than that of the other two groups. The distribution of beta2/3 immunoreactivity was similar to that of alpha1. beta2/3 immunolabeling in the neuronal soma from the schizophrenia and bipolar disorder groups was more intense than that of the normal controls. The densitometry measurements, as well as the immunoblot analysis for alpha1 and beta2/3 were highly consistent with the alpha1 and beta2/3 immunohistochemistry results. The present study suggests that the expression of these two GABA(A) receptor subunits was altered in subjects with schizophrenia and bipolar disorder, but that the patterns of change differed between those with these two disorders.
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http://dx.doi.org/10.1016/j.neures.2004.06.006DOI Listing
September 2004

GABAA receptor gamma subunits in the prefrontal cortex of patients with schizophrenia and bipolar disorder.

Neuroreport 2004 Aug;15(11):1809-12

Department of Psychiatry, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba City, Ibaraki 305-8575, Japan.

Immunohistochemical and immunoblot techniques were employed in order to examine alterations of the GABAA receptor gamma subunits in the prefrontal cortex from postmortem subjects with schizophrenia and bipolar disorder. Immunohistochemically, gamma 1/3 immunolabeling in the neuronal soma in the prefrontal cortex from subjects with bipolar disorder was more intense than that of the controls and the subjects with schizophrenia. The intensity of gamma 1/3 immunolabeling of the schizophrenic subjects was comparable with that of the controls. Immunoblot analysis demonstrated a significant increase in the gamma 1 subunit in the bipolar subjects, whereas no remarkable difference was detected in the schizophrenic subjects. The present study suggests that the GABAA receptor gamma subunit is differentially involved in schizophrenia and bipolar disorder, and that the gamma subunit is up-regulated in the prefrontal cortex of subjects with bipolar disorder.
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http://dx.doi.org/10.1097/01.wnr.0000135695.66366.08DOI Listing
August 2004
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