Masahiro Kokai

Features of obsessive-compulsive disorder in patients primarily diagnosed with schizophrenia

Abstract We investigated the prevalence of obsessive–compulsive disorder (OCD) among patients who were primarily diagnosed with schizophrenia. We investigated the differences in the neuropsychiatric features and motor symptoms between patients with schizophrenia who did or did not have OCD. Seventy‐one subjects with the DSM‐IV diagnosis of schizophrenia were evaluated by the Structured Clinical Interview for DSM‐IV Axis I Disorders, the Yale‐Brown Obsessive–compulsive Scale and the Positive and Negative Syndrome Scale. To assess their motor symptoms, the Abnormal Involuntary Movements Scale, the Barnes rating scale for drug‐induced akathisia and the Simpson and Angus extrapyramidal symptoms (EPS) rating scale were used. The 13 subjects with OCD (18.3%) had significantly more severe motor symptoms than the non‐OCD subjects. Patients with schizophrenia who exhibit moderate to severe motor symptoms as side‐effects of neuroleptics, should be examined for OCD comorbidity. Patients who are found to have OCD comorbidity must be treated with carefully chosen medications, including serotonin re‐uptake inhibitors.

Plasma interleukin-18 levels in patients with psychiatric disorders.

There are an increasing number of reports on an association between the alteration of circulating cytokine levels and pathophysiology of psychiatric disorders. Plasma concentrations of interleukin (IL)-18 were measured in 13 nonmedicated patients with psychiatric disorders. There was a significant elevation of IL-18 levels in patients with major depression (n = 8) and panic disorder (n = 5), compared with normal controls. The mean IL-18 value of our psychiatric patients was comparable with that of various somatic disorders reported. We suggest that the elevation of plasma IL-18 levels reflects the increased production and release of IL-18 in the central nervous system under stressful settings. We propose that the measurement of IL-18 plasma levels may provide a useful index for the involvement of immune system in psychiatric disorders.

Natural disaster and mental health in Asia

Abstract  The purpose of the present article was to review the literature on disaster mental health in relation to natural disasters such as earthquakes, volcanic eruptions, typhoons and cyclones throughout Asia. Articles reviewed show that disaster psychiatry in Asia is beginning to emerge from and leave behind the stigma attached to mental health. The emergence of the acceptance of disaster mental health throughout Asia can be attributed in part to the acceptance of the notion of post‐traumatic stress disorder (PTSD). This has allowed greater involvement of mental health professionals in providing ongoing support to survivors of natural disasters as well as providing greater opportunities for further research. Also, articles reviewed in the present paper commonly suggested the need for using standardized diagnostic tools for PTSD to appropriately interpret the discrepancy of results among studies. The importance of post‐disaster support services and cultural differences is highlighted.

Synapse alteration in hippocampal CA3 field following entorhinal cortex lesion

To model one aspect of the neurodegeneration observed in Alzheimers disease and to investigate the synaptic alteration of the hippocampus associated with entorhinal cortex lesion, ibotenic acid was used to produce selective unilateral neuronal loss in rat entorhinal cortex. Immunohistological and microdensitometrical analyses confirmed ibotenic acid lesion of the entorhinal cortex after 3 months and showed a decrease of synaptophysin-immunoreactive substances in the stratum lucidum of the CA3 field. This study demonstrates that entorhinal cortex lesion can lead to synaptic alterations and cause damage to presynaptic terminals with projecting area in the disruption of the entorhinal cortex hippocampus relay passage.

Immunophenotypic studies on atypical lymphocytes in psychiatric patients

By using phase-contrast microscopy combined with a fluorescent staining technique, the frequency of blast-type atypical lymphocytes (BTALs) appearing in peripheral blood and the phenotypic expression of their surface antigens were studied in 24 patients with schizophrenia, 16 with mood disorder and 14 healthy controls. BTALs were classified as being stimulated or activated cells, morphologically characterized by their large size, dark cytoplasm, a hollow perinuclear containing a few granules and finely dispersed chromatin structures with a few evident nucleoli. A significantly higher number of BTALs were found in the schizophrenic patients compared with healthy control subjects or patients with mood disorder. Further, there was a significant difference in the frequency of BTALs between patients with mood disorder and healthy control subjects. No significant difference in the frequency of BTALs was found between the schizophrenic patients with and without medication. Immunostaining of BTALs revealed that these cells consisted of B, T and non-B, non-T cell subpopulations. Contrary to our expectations, the T cell was only one third of the BTAL population. HLA-DR and CD38 were expressed on most BTALs (> 70%), while CD25, an early activation marker of T cells was rarely found on BTALs (< 0.3%). The differences in activated lymphocyte populations which appeared as morphologically atypical in the circulation among some psychiatric patients and infectious or autoimmune diseases are discussed. This is the first report on populations of BTALs.

α-Synuclein-positive structures induced in leupeptin-infused rats

Abnormal accumulation of alpha-synuclein is regarded as a key pathological step in a wide range of neurodegenerative processes, not only in Parkinsons disease (PD) and dementia with Lewy bodies (DLB) but also in multiple-system atrophy (MSA). Nevertheless, the mechanism of alpha-synuclein accumulation remains unclear. Leupeptin, a protease inhibitor, has been known to cause various neuropathological changes in vivo resembling those of aging or neurodegenerative processes in the human brain, including the accumulation of neuronal processes and neuronal cytoskeletal abnormalities leading to neurofibrillary tangle (NFT)-like formations. In the present study, we administered leupeptin into the rat ventricle and found that alpha-synuclein-positive structures appeared widely in the neuronal tissue, mainly in neuronal processes of the fimbria and alveus. Immunoelectron microscopic study revealed that alpha-synuclein immunoreactivity was located in the swollen axons of the fimbria and alveus, especially in the dilated presynaptic terminals. In addition colocalization of alpha-synuclein with ubiquitin was rarely observed in confocal laser-scan image. This is the first report of experimentally induced in vivo accumulation of alpha-synuclein in non-transgenic rodent brain injected with a well-characterized protease inhibitor by an infusion pump. The present finding suggests that the local accumulation of alpha-synuclein might be induced by the impaired metabolism of alpha-synuclein, which are likely related to lysosomal or ubiquitin-independent proteasomal systems.

A Morphometric study of subcortical neurofibrillary tangles in Alzheimer's disease

The numbers of neurofibrillary tangles(NFT) in the subcortical nuclei detected in Gallyas‐Nissl double stained sections was evaluated with computer‐based image analysis techniques. This was undertaken to examine the susceptibility to NFT formation and to identify mutual correlations in NFT formation among the basal ganglia in Alzheimers disease (AD). The numbers of NFT are insufficient to compare the regional differences of NFT in each nucleus of the AD brains because large subcortical gray nuclei tend to have more NFT, Incidences of NFT were given definitions in order to find the NFT incidences for the expected neuronal populations, The definitions used were: the ratio of total numbers of NFT observed in a given subcortical gray nucleus of AD brains to the total numbers of medium‐ to large‐sized neurons(≥ 150μm2) in which the nucleoli were confirmed in the corresponding structure of control brains. A common order of susceptibility to NFT changes was found among the subcortical nuclei in advanced stages of AD cases, According to NFT incidences, subcortical nuclei were classified into four groups. The highest incidence of NFT (88%) was found in the nucleus basalis of Meynert. The severely affected group (NFT Incidences; 28–44%) included the raphe nucleus (superior central nucleus), anterior thalamic nucleus (anterior ventral thalamic nucleus), locus ceruleus and claustrum, The putamen, substantia nigra (zona compacta), medial thalamic nucleus (medio‐dorsal thalamic nucleus) and lateral thalamic nucleus (ventro‐lateral and ventro‐anterior thalamic nuclei) comprised the moderately affected group (NFT incidences; 9–15%). The substantia nigra (zona reticulata), globus pallidus, subthalamic nucleus and red nucleus constituted the slightly affected group (NFT incidences;<5%). In spite of the group classifications, no significant mutual correlations in NFT incidences between any pair of subcortical nuclei were indicated. The present study suggests that the NFT formations in AD take place in the subcortical nuclei according to individual susceptibility, irrespective of the connections between the nuclei.

The cell cycle-related genes as biomarkers for schizophrenia.

BACKGROUND Recent studies suggest that genomic abnormalities such as single nucleotide polymorphisms (SNPs) and copy number variations (CNVs) may elevate the risk of schizophrenia. Such genomic abnormalities often occur during chromosomal DNA replication in the S phase of cell cycle. In addition, several studies showed that abnormal expressions of several cell cycle-related genes are associated with schizophrenia. Therefore, here we compared mRNA expression levels of cell cycle-related genes in peripheral blood cells between patients with schizophrenia and healthy controls. METHOD mRNA expression levels of cell cycle-related genes in peripheral blood cells from patients with schizophrenia and healthy controls were measured with quantitative reverse transcription polymerase chain reaction (Q-RT-PCR). The discovery, replication and intervention studies with Q-RT-PCR were performed as follows: discovery (40 cases and 20 controls), replication (82 cases and 74 controls) and intervention (22 cases and 18 controls). RESULT Nine genes were identified in the discovery and replication stages as schizophrenia-associated genes. Moreover, the combination of mRNA expression levels of CDK4, MCM7 and POLD4 was identified as a potential biomarker for schizophrenia with multivariate logistic regression analysis. The intervention stage revealed that the mRNA expression levels of these three genes were significantly decreased in the acute state of schizophrenia, and CDK4 was significantly recovered in the remission state of schizophrenia. CONCLUSION The combination of mRNA expression levels of three cell cycle-related genes such as CDK4, MCM7 and POLD4 is expected to be a candidate for useful biomarkers for schizophrenia. Especially, the mRNA expression changes of CDK4 may be potential as both trait and state markers for schizophrenia.

A morphometric study of subcortical changes in Alzheimer's disease

The populations and loss of neurons, the density of neurofibrillary tangles (NFT) and senile plaque (SP), and the macroscopic shrinkage of the subcortical areas in patients with Alzheimers disease (AD) were quantitatively evaluated using computer‐based image analysis techniques. Twelve subcortical areas were examined at distinct levels of the brain in eight AD cases and five age‐matched controls. The areas examined were as follows: the nucleus basalis of Meynert (nbM); globus pallidus (GP); putamen (PT); claustrum (CL); the anterior thalamic nucleus (THA: anterior ventral thalamic nucleus); medial thalamic nucleus (THM: medio‐dorsal thalamic nucleus); lateral thalamic nucleus (THL: ventro‐lateral and ventro‐anterior thalamic nuclei); subthalamic nucleus (ST); substantia nigra, zona compacta (SNC); red nucleus (RD); locus ceruleus (LC); and raphe nucleus (RP). Distinct neuronal loss and a high density of NFT were shown in the nbM, LC, RP, CL, SNC, and THA in the AD brain. Because of the high density of the NFT relative to the neuronal loss, neuronal loss in those nuclei may have been mainly caused by NFT formation. In the THM and THL, no distinct neuronal loss but some degree of NFT formations was detected. In the GP, ST, and RD, neuronal shrinkage or loss was shown in patients with AD. With respect to the SP, the density of SP in the CL, PT and THM was high (1.7–2.2%), whereas that in the SNC, GP, ST and RD was low. This finding suggests that SP may not have major effects on the neuronal degeneration observed in subcortical nuclei of patients with AD. Although macroscopic shrinkage of all subcortical nuclei was seen in AD patients, selective vulnerability to atrophic change was not evident at macroscopic levels. This comprehensive morphometric study offers more precise information for evaluating the subcortical dysfunction in AD patients than do conven‐tional neuropathological examinations.