Shinichiro Ochi

DNA methylation changes at SNCA intron 1 in patients with dementia with Lewy bodies

It is difficult to diagnose dementia with Lewy bodies (DLB) because it exhibits clinical and neuropathological overlap with both Alzheimers disease and Parkinsons disease. The α‐synuclein protein is a major component of Lewy bodies, and accumulation of α‐synuclein aggregates causes synaptic dysfunction in DLB. Epigenetic changes at the synuclein alpha ( SNCA ) gene may be involved in DLB pathogenesis.

Different actions for acute and chronic administration of mirtazapine on serotonergic transmission associated with raphe nuclei and their innervation cortical regions.

The atypical antidepressant, mirtazapine enhances noradrenergic transmission, but its effects on serotonergic transmission remain to be clarified. The present study determined the effects of acute and chronic administration of mirtazapine on serotonergic transmissions in raphe nuclei and their innervation regions, frontal and entorhinal cortex, using multiple-probes microdialysis with real-time PCR and western blotting. Acute administration of mirtazapine did not affect extracellular serotonin level in raphe nuclei or cortex; however, chronic administration increased extracellular serotonin level in raphe nuclei without affecting that in cortex. Blockade of 5-HT1A receptor, but not that of the 5-HT2A/2C receptor, enhanced the effects of acute administration of mirtazapine on extracellular serotonin level in raphe nuclei. Chronic mirtazapine administration reduced the inhibitory function associated with somatodendritic 5-HT1A receptor in raphe nuclei, but enhanced postsynaptic 5-HT1A receptor in serotonergic innervated cortical regions. Chronic administration reduced the expression of mRNA and protein of serotonin transporter and 5-HT1A receptor in raphe nuclei, but not in the cortices. These results suggested that acute administration of mirtazapine probably activated serotonergic transmission, but its stimulatory action was abolished by activated inhibitory 5-HT1A receptor. Chronic administration of mirtazapine resulted in increased extracellular serotonin level via reduction of serotonin transporter with reduction of somatodendritic 5-HT1A autoreceptor function in raphe nuclei. These pharmacological actions of mirtazapine include its serotonergic profiles as noradrenergic and specific serotonergic antidepressant (NaSSA).

TREM2 mRNA Expression in Leukocytes Is Increased in Alzheimer’s Disease and Schizophrenia

TREM2 and TYROBP are causal genes for Nasu–Hakola disease (NHD), a rare autosomal recessive disease characterized by bone lesions and early-onset progressive dementia. TREM2 forms a receptor signaling complex with TYROBP, which triggers the activation of immune responses in macrophages and dendritic cells, and the functional polymorphism of TREM2 is reported to be associated with neurodegenerative disorders such as Alzheimer’s disease (AD). The objective of this study was to reveal the involvement of TYROBP and TREM2 in the pathophysiology of AD and schizophrenia. Methods: We investigated the mRNA expression level of the 2 genes in leukocytes of 26 patients with AD and 24 with schizophrenia in comparison with age-matched controls. Moreover, we performed gene association analysis between these 2 genes and schizophrenia. Results: No differences were found in TYROBP mRNA expression in patients with AD and schizophrenia; however, TREM2 mRNA expression was increased in patients with AD and schizophrenia compared with controls (P < 0.001). There were no genetic associations of either gene with schizophrenia in Japanese patients. Conclusion: TREM2 expression in leukocytes is elevated not only in AD but also in schizophrenia. Inflammatory processes involving TREM2 may occur in schizophrenia, as observed in neurocognitive disorders such as AD. TREM2 expression in leukocytes may be a novel biomarker for neurological and psychiatric disorders.

No abnormal hexanucleotide repeat expansion of C9ORF72 in Japanese schizophrenia patients

Abnormal hexanucleotide repeat expansion of C9ORF72 is known to cause neurodegenerative disorders such as frontotemporal dementia. Additionally, patients with psychotic symptoms are more likely to have abnormal hexanucleotide repeat expansion than are patients without them. We investigated the hexanucleotide repeat sizes of C9ORF72 in 466 Japanese schizophrenia patients. We found no abnormal hexanucleotide repeat expansion. In conclusion, C9ORF72 may not be responsible for schizophrenia susceptibility in the Japanese population.

Gene Expression and Methylation Analysis of ABCA7 in Patients with Alzheimer’s Disease

BACKGROUND/OBJECTIVE The aim of this study was to examine the blood gene expression and methylation of ATP-binding cassette sub-family A member 7 gene (ABCA7) as a biological marker of AD. METHODS AD subjects (n = 50; 11 males, 77.7±6.05 years old) and age- and sex-matched healthy controls (n = 50) were recruited. A single nucleotide polymorphism in ABCA7 (rs3764650), methylation rates of CpG sites in the ABCA7 promoter region, and ABCA7 mRNA expression levels in peripheral blood were examined. RESULTS The distribution of the rs3764650 polymorphism in AD subjects was not different from that of controls. Although the methylation rates of AD subjects were not significantly different from those of controls, the ABCA7 mRNA expression level in AD subjects was significantly higher than that in controls. Additionally, the ABCA7 mRNA expression level in AD subjects was significantly correlated with Mini-Mental State Examination recall, the Alzheimers Disease Assessment Scale total score, and the Clinical Dementia Rating score. We also found a significant correlation between the ABCA7 mRNA expression level and duration of illness. CONCLUSION The ABCA7 mRNA expression level in peripheral blood may be a marker for early stages of AD and disease progression regardless of rs3764650 and the methylation rate of its promoter.

The nicotinic cholinergic system is affected in rats with delayed carbon monoxide encephalopathy

Delayed carbon monoxide (CO) encephalopathy may occur following recovery from acute CO poisoning. However, the mechanism of delayed neuronal injury remains unknown. The nicotinic acetylcholine receptors (nAChRs) have been suggested to play a role in cognitive status in neurodegenerative diseases, including Alzheimers disease. Therefore, in the current study, we investigated the effect of delayed neuronal CO poisoning on gene expression of nAChRs in the hippocampus of Wistar rats. Behavioral effects (measured by the passive-avoidance test) and histological analyses (hematoxylin-eosin-stained hippocampal cell counts and cell death observations) were also investigated, 21 days after CO exposure for 1h (1000ppm for 40min+3000ppm for 20min). Our findings show cognitive impairment and hippocampal cell death, suggesting our rat model is suitable for studying delayed CO encephalopathy. Expression of nAChR (Chrna3, Chrna4, Chnra7, and Chrnb2) mRNA was assessed using quantitative real-time polymerase chain reaction. Hippocampal Chrna3 expression was significantly decreased, and cerebellar Chrna7 expression significantly increased, in the delayed CO encephalopathy rat model. Thus, the nicotinic cholinergic system may be affected in delayed CO encephalopathy.

Antidepressant action via the nitric oxide system: A pilot study in an acute depressive model induced by arginin.

Nitric oxide (NO) may be a neurotransmitter related to major depressive disorder (MDD) because the selective neuronal NO synthase (NOS) inhibitor, 7-nitroindazole, induces dose-dependent antidepressant-like effects. However, its role in MDD is not yet known. The purpose of our study was to determine if antidepressants improve depression via the NO pathway using an acute depressive rat model induced by L-arginine (AR). Three types of antidepressants were examined, fluoxetine (FLX, 10 mg/kg), milnacipran (MIL, 30 mg/kg), and mirtazapine (MIR, 10 mg/kg), in a depressive model that used AR (750 mg/kg) pretreatment. mRNA expression levels of three NOS subtypes were analyzed by real-time PCR, as well as serum NO levels. Significant increases in iNOS mRNA expression levels were found in brain regions after AR treatment, although the eNOS gene tended to decrease with AR injection. After antidepressant treatment, there were no mRNA expression changes in either nNOS or iNOS. However, eNOS mRNA expression significantly increased with FLX (cerebellum, P=0.011; hippocampus, P=0.011; midbrain, P=0.011; pons, P=0.013; striatum, P=0.011; and thalamus, P<0.001). There was a statistically significant increase in serum NO levels with MIL treatment (P=0.011). We conclude that changes in eNOS mRNA levels in the brain with FLX treatment, and amount of serum NO with MIL treatment may be related to antidepressant effects of both agents, but further experiments are needed to confirm involvement of the NO system in MDD.

A case study: neuroleptic malignant syndrome with risperidone and CYP2D6 gene variation.

We present a schizophrenic patient who experienced neuroleptic malignant syndrome with risperidone treatment due to variants of the CYP2D6 gene with reduced function. Clinicians need to be aware of this potential complication.

Metabolic status and resistin in chronic schizophrenia over a 2-year period with continuous atypical antipsychotics

Background: Common adverse effects of atypical antipsychotic treatments for schizophrenia are weight gain and lipid metabolism abnormality. We aimed to identify the signs of metabolic problems with continuous atypical antipsychotic treatment for schizophrenia over a 2-year period. Methods: The participants were 68 schizophrenic patients (29 males, 39 females; ages 53.4 ± 13.5 years old). Changes in carbohydrate metabolism and changes in physical characteristics were studied over a 2-year period. In addition, functional single nucleotide polymorphisms in the transcriptional regulatory region of the resistin gene were examined. Results: We found no changes in the mental state of the participants over a 2-year period. Patients did show a significant decrease in total cholesterol and hemoglobin A1c levels, although physical changes such as body mass index and abdominal girth, were not observed. The amount of resistin may not be associated with mental states and physical parameters. Conclusions: We could not find physical factors related to metabolic changes of antipsychotics in this 2-year study. However, several psychological factors, such as health-related thoughts and behaviors, should be studied in the future.

Combined clozapine and electroconvulsive therapy in a Japanese schizophrenia patient: a case report.

Clozapine is well-known for successful use in schizophrenic patients treatment resistant to other antipsychotics. However, even with clozapine, 25% of schizophrenic patients are not in remission. Recently, as adjunctive treatment with clozapine, electroconvulsive therapy has been reported to be an effective and safe adjunctive treatment. We report a Japanese schizophrenic woman who was not in remission with clozapine alone but with both clozapine and electroconvulsive therapy.