Shin Hidaka

Immunohistochemical localization of GABAB receptor in the entorhinal cortex and inferior temporal cortex of schizophrenic brain.

Immunocytochemical techniques were employed to examine the changes in immunolabeling of the gamma-aminobutyric acid (GABA)B receptor within the entorhinal cortex and inferior temporal isocortex of the schizophrenic brain. In the entorhinal cortex of the control subjects, an intense immunoreactivity was observed in the soma and processes of stellate cells in Layer II, in pyramidal cells in Layers II, III, and V, and in nonpyramidal interneurons. In subjects with schizophrenia, GABA(B) immunoreactivity was markedly reduced in pyramidal cells throughout the layers. In the inferior temporal cortex of the controls, both pyramidal cells and nonpyramidal interneurons demonstrated an intense immunoreactivity, while in the same region of the schizophrenic brain a marked reduction of the GABA(B) immunolabeling was observed in pyramidal cells in Layer V. These findings suggest that in the entorhinal cortex and the inferior temporal cortex of the schizophrenic brain, the expression of the GABA(B) receptor is reduced, and raise the possibility that GABA(B) receptor dysfunction is involved in the pathophysiology of schizophrenia.

Immunohistochemical and immunoblot study of GABAA α1 and β2/3 subunits in the prefrontal cortex of subjects with schizophrenia and bipolar disorder

A number of investigations have provided a growing body of evidence of the involvement of the γ-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 GABAA receptor α1 and β2/3 subunits in the prefrontal cortex from postmortem subjects with schizophrenia and bipolar disorder. α1 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. α1 immunolabeling in the neuronal soma from the schizophrenic group was more intense than that of the other two groups. The distribution of β2/3 immunoreactivity was similar to that of α1. β2/3 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 α1 and β2/3 were highly consistent with the α1 and β2/3 immunohistochemistry results. The present study suggests that the expression of these two GABAA receptor subunits was altered in subjects with schizophrenia and bipolar disorder, but that the patterns of change differed between those with these two disorders.

Immunohistochemical localization of γ-aminobutyric acidB receptor in the hippocampus of subjects with schizophrenia

Recent studies have demonstrated the involvements of gamma-aminobutyric acid (GABA) neurotransmitter systems in the schizophrenic brain. In order to further elucidate the alterations of this system in schizophrenia, we employed immunohistochemical techniques and examined the expression and anatomical distribution of the GABA(B) receptor in the hippocampus of five subjects with schizophrenia and three age-matched controls. In the control hippocampus, the most intense immunoreactivity was observed in the soma and processes of multipolar interneurons throughout the hippocampus. Pyramidal cells too were intensely labeled in their soma and proximal portion of dendrites, although the labeling intensity was varied in each subregion. For example, in the CA1 subfield, the labeling intensity of pyramidal cells was much less intense than that in the CA3 and CA2 subfields. In the subjects with schizophrenia, GABA(B) immunoreactivity was markedly reduced in granule cells as well as in pyramidal cells throughout the CA fields. In interneurons, GABA(B) labeling was relatively preserved compared to that in pyramidal cells. Our findings suggest that in the hippocampus of schizophrenic patients the expression of the GABA(B) receptor is reduced, and raise the possibility that this reduction contributes to the pathophysiological process in the schizophrenic brain.

Prevalence of four subtypes of mild cognitive impairment and APOE in a Japanese community.

The results of previous reports estimating the prevalence of mild cognitive impairment (MCI) have varied widely according to the criteria used to define MCI.

Dementia and mild cognitive impairment among non-responders to a community survey

We aimed to estimate the prevalence of mild cognitive impairment (MCI) among elderly non-responders to a community-based survey. We conducted a two-phase, population-based cross-sectional study of community-dwelling individuals aged 65 years or older in Tone, located in central Japan. The first phase of the study consisted of physical and cognitive examinations of individuals who responded to the first recruitment (quick-responders), whereas the second phase included individuals who did not respond in the first phase (delayed-responders). We compared the prevalence of MCI and dementia between delayed-responders and quick-responders. Of the 2,698 potential candidates, 1,888 (1,619 quick-responders, 225 delayed-responders, and 44 nursing home residents) were enrolled (70.0%). The prevalence of MCI was 2.3-fold increased in delayed-responders compared to the quick-responders (OR=2.27, 95% CI: 1.37-3.77, p=0.002, aged< or =74). In order to develop a method for the early detection of dementia, we must pay more attention to delayed-or non-responders.

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

Alterations in the γ-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 GABAB 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.

Prevalence of depression and depressive symptoms among older Japanese people: comorbidity of mild cognitive impairment and depression.

The aim of the study was to estimate the prevalence of DSM‐III‐R major depressive episodes (MDEs), depressive symptoms cases (DSCs) (defined as a score of ≥6 on the Geriatric Depression Scale but falling short of MDE), and coexisting mild cognitive impairment (MCI) among Japanese community‐dwelling older people.

Effect of plasma lipids, hypertension and APOE genotype on cognitive decline.

We examined the combined effect of plasma lipids/hypertension and apolipoprotein E (APOE) genotype on cognitive function in elderly individuals. Plasma concentrations of high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglyceride (TG), total cholesterol (TC), APOE, and history of hypertension were evaluated in 622 community-dwelling individuals aged 65 years and older. We investigated the associations between plasma lipids/hypertension and cognitive function in apolipoprotein E4 allele (APOE4) carrier (E4+) and APOE4 noncarrier (E4-) groups using 3-year longitudinal data. At baseline and 3 years later, cognitive scores were correlated with plasma APOE levels in both E4- and E4+, and HDL level in E4-. The combination of hypertension and E4+, but not E4-, was associated with a significant deterioration in cognitive function during the 3-year follow-up. Our findings suggest that an interaction between APOE and HDL is facilitated by APOE4, and is possibly linked with a protective effect on cognitive decline in later life. The findings also indicate a synergistic effect of an APOE4 allele and hypertension on the acceleration of cognitive decline.

Association between cognitive function and plasma lipids of the elderly after controlling for apolipoprotein E genotype.

OBJECTIVE Although the relationship between cognitive function and plasma lipids has attracted attention, previous studies have shown conflicting results. One possible confounding factor is due to the influence of gene-related modulator. We investigated the relationship between cognitive function and lipid plasma levels of old age after controlling for apolipoprotein E (APOE) genotype. METHODS One thousand three hundred ninety-five subjects without dementia age 65 and older participated in this study. They were divided into two groups, with and without APOE4 [E4 (+) and E4 (-)]. Plasma concentrations of high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglyceride (TG), total cholesterol (TC) and apolipoprotein E (apoE) were measured. Associations between plasma concentrations of lipids and cognitive function were investigated for each group. RESULTS We found a positive association between cognitive scores and plasma apoE level in both E4 (-) and E4 (+) groups. A positive relationship was also observed between cognitive score and HDL level in the E4 (-) group, but not in the E4 (+) group. No substantial association between cognitive score and LDL, TG, and TC levels was found in either of the groups. CONCLUSIONS Our findings suggest that plasma apoE have a positive influence on cognitive function in both E4 (-) and E4 (+) groups, whereas the positive influence of plasma HDL was shown only in E4 (-) group. The identification of the influences of (APOE) genotype and the intracellular linkage among apoE and HDL metabolism is hoped for new preventive and therapeutic strategies for cognitive change of elderly.

Alterations of NMDAR1 and NMDAR2a/B immunoreactivity in the hippocampus after perforant pathway lesion.

Immunohistochemical techniques were employed to examine the changes in immunolabeling of the N‐methyl‐d‐aspartate (NMDA) receptor subunits NMDAR1 and NMDAR2A/B within the hippocampus 1, 3, 7, 14 and 30 days after a unilateral perforant pathway lesion was made in a rat brain. At 1 day post‐lesion, we observed a decrease in NMDAR1 immunolabeling in the granule cells in the dentate gyrus as well as in the mossy cells in the polymorphic region ipsilateral to the lesion, while an increase in diffuse neuropil labeling was observed. At 3 days post‐lesion, we observed a marked increase in NMDAR1 immunolabeling in the outer molecular layer of the dentate gyrus as well as in the stratum moleculare in the CA fields ipsilateral to the lesion. Although this increase was less marked at 7 and 14 days post‐lesion, an increase in NMDAR1 immunolabeling was evident at 30 days post‐lesion. In contrast, although a transient increase in NMDAR2A/B immunolabeling was observed in the outer molecular layer at 3 days post‐lesion, no other changes were detectable at any of the time points examined. Our study suggests that each subunit of the NMDA receptor displays a different response to deafferentation of the perforant pathway. We have previously observed that changes in the immunoreactivity of the receptor subunits of another class of glutamate receptor, α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoaxolepropionate (AMPA), occur at 30 days post‐lesion but not after a relatively short survival time. NMDA receptor subunits demonstrate an earlier response to the loss of the perforant pathway fibers than do the AMPA receptor subunits.