Shigeto Yamada

Neuroinflammation in schizophrenia especially focused on the role of microglia

An accumulating body of evidence point to the significance of neuroinflammation and immunogenetics also in schizophrenia. Recent genome-wide studies in schizophrenia suggest immune involvement in schizophrenia. Microglia are the resident macrophage of the brain and major players in innate immunity in the CNS. They respond rapidly to even minor pathological changes in the brain and may contribute directly to the neuronal degeneration by producing various pro-inflammatory cytokines and free radicals. In many aspects, the neuropathology of schizophrenia is closely associated with microglial activation. We and other researchers have shown the inhibitory effects of some typical or atypical antipsychotics on the release of inflammatory cytokines and free radicals from activated microglia, both of which are not only directly toxic to neurons but also cause a decrease in neurogenesis as well as white matter abnormalities in the brains of the patients with schizophrenia. The treatment through the inhibition of microglial activation may shed new light on the therapeutic strategy of schizophrenia.

Genomewide High-Density SNP Linkage Analysis of 236 Japanese Families Supports the Existence of Schizophrenia Susceptibility Loci on Chromosomes 1p, 14q, and 20p

The Japanese Schizophrenia Sib-Pair Linkage Group (JSSLG) is a multisite collaborative study group that was organized to create a national resource for affected sib pair (ASP) studies of schizophrenia in Japan. We used a high-density single-nucleotide-polymorphism (SNP) genotyping assay, the Illumina BeadArray linkage mapping panel (version 4) comprising 5,861 SNPs, to perform a genomewide linkage analysis of JSSLG samples comprising 236 Japanese families with 268 nonindependent ASPs with schizophrenia. All subjects were Japanese. Among these families, 122 families comprised the same subjects analyzed with short tandem repeat markers. All the probands and their siblings, with the exception of seven siblings with schizoaffective disorder, had schizophrenia. After excluding SNPs with high linkage disequilibrium, we found significant evidence of linkage of schizophrenia to chromosome 1p21.2-1p13.2 (LOD=3.39) and suggestive evidence of linkage to 14q11.2 (LOD=2.87), 14q11.2-q13.2 (LOD=2.33), and 20p12.1-p11.2 (LOD=2.33). Although linkage to these regions has received little attention, these regions are included in or partially overlap the 10 regions reported by Lewis et al. that passed the two aggregate criteria of a meta-analysis. Results of the present study--which, to our knowledge, is the first genomewide analysis of schizophrenia in ASPs of a single Asian ethnicity that is comparable to the analyses done of ASPs of European descent--indicate the existence of schizophrenia susceptibility loci that are common to different ethnic groups but that likely have different ethnicity-specific effects.

Multicentre population-based dementia prevalence survey in Japan: a preliminary report

Community‐based surveys were performed in seven rural areas in Japan to investigate the prevalence of dementia and illnesses causing dementia. A total of 5431 elderly subjects were selected based on census data from 1 October 2009. In total, 3394 participants were examined (participation rate: 62.5%), and 768 dementia cases and 529 mild cognitive impairment cases were identified. Of the illnesses causing dementia, Alzheimers disease was the most frequent (67.4%), followed by vascular dementia (18.9%), dementia with Lewy body disease (4.6%), mixed dementia (4.2%) and other illnesses. The prevalence of dementia according to 5‐year age strata between 65 and 99 years was 5.8–77.7% among the participants. The prevalence of dementia in this study was higher than in previous reports in Japan and other countries. To verify the upward trend of dementia prevalence and its background factors, we have scheduled surveys for three other urban areas in 2011–2012.

Involvement of the Noradrenergic System in Performance on a Continuous Task Requiring Effortful Attention

To determine the effects of noradrenergic neuronal activity on performance in continuous tasks requiring effortful attention, the performance of 23 male students in the Uchida-Kraepelin test (UKT) was examined. The UKT requires continuous arithmetic addition of single-digit figures for 25 min. The relationship of performance with saliva levels of 3-methoxy-4-hydroxyphenylglycol (sMHPG) was analyzed. Saliva samples were taken before, during and after test performance, and sMHPG levels determined by gas chromatography-mass spectrometry. There was no significant change in mean sMHPG as a result of test performance. However, when initial effort was calculated, defined as number of items completed during the 1st min subtracted from the average completed per minute in the 1st and the 2nd halves (blocks) of the test, significant correlations with sMHPG (p = 0.0002 for the 1st block and p < 0.0001 for the 2nd block) were found. Thus the data indicate that noradrenergic neuronal activity affects the performance on continuous tasks requiring effortful attention.

Possible Role of BDNF-Induced Microglial Intracellular Ca 2+ Elevation in the Pathophysiology of Neuropsychiatric Disorders

Microglia are intrinsic immune cells that release factors, including proinflammatory cytokines, nitric oxide (NO) and neurotrophins, following activation after disturbance in the brain. Elevation of intracellular Ca(2+) concentration ([Ca(2+)]i) is important for microglial functions, such as the release of cytokines and NO from activated microglia. There is increasing evidence suggesting that pathophysiology of neuropsychiatric disorders is related to the inflammatory responses mediated by microglia. Brain-derived neurotrophic factor (BDNF) is a neurotrophin well known for its roles in the activation of microglia as well as in pathophysiology and/or treatment of neuropsychiatric disorders. We have recently reported that BDNF induces a sustained increase in [Ca(2+)]i through binding with the truncated TrkB receptor, resulting in activation of the PLC pathway and store-operated calcium entry (SOCE) in rodent microglial cells. Sustained activation of SOCE, possibly mediated by TRP channels, occurred after brief BDNF application and contributed to the maintenance of sustained [Ca(2+)]i elevation. Pretreatment with BDNF significantly suppressed the release of NO from activated microglia. Additionally, selective serotonin reuptake inhibitors (SSRIs), including paroxetine or sertraline, potentiated the BDNF-induced increase in [Ca(2+)]i in rodent microglial cells This article provides a review of recent findings on the role of BDNF in the pathophysiology of neuropsychiatric disorders, especially by focusing on its effect on intracellular Ca(2+) signaling in microglial cells.

Association between the scores on the general health questionnaire-28 and the saliva levels of 3-methoxy-4-hydroxyphenylglycol in normal volunteers.

To access the saliva level of 3-methoxy-4-hydroxy-phenylglycol (sMHPG) as an index of mental health in normal volunteers, we investigated the relationship between the sMHPG and the scores on the general health questionnaire-28 (GHQ-28). A total of 270 normal volunteers answered the GHQ-28 and the sMHPG levels were determined. The sMHPG levels in women and men were comparable. There was a significant negative correlation between the social dysfunction score on the GHQ-28 and sMHPG levels in women (P=0.0035), but not in men. Moreover, the sMHPG levels also correlated with the total GHQ-28 score (P=0.0205), the anxiety and the insomnia score (P=0.0306) in women. These data indicate a high social dysfunction score on the GHQ-28 to be associated with a reduced noradrenergic neuronal tone thus possibly reflecting psychomotor retardation in women.

Association of inflammatory biomarkers with depressive symptoms and cognitive decline in a community-dwelling healthy older sample: A 3-year follow-up study

BACKGROUND The relationship between the pathophysiology of dementia and neuroinflammation is well-known. The number of reports stating that depression is a risk factor for dementia has recently been increasing. These epidemiological findings suggest the possibility that both depression and dementia have common pathophysiological backgrounds of neuroinflammation. METHODS The sample consists of 64 non-demented community-dwelling older participants aged 65 years or over. Participants were assessed at baseline (2004-2006) and 3 years later (2007-2009). Plasma concentration of markers of inflammation (interleukins (IL)-1β, IL-2, IL-6, soluble interleukin-2 receptor (sIL-2R), soluble interleukin-6 receptor (sIL-6R), high sensitivity C-reactive protein (hsCRP) and tumor necrosis factor (TNF)-α) were measured at baseline. Depression symptoms were assessed with the Beck Depression Inventory (BDI) and cognitive decline was assessed with the Mini-Mental State Examination (MMSE), Frontal Assessment Battery (FAB) and Clock Drawing Test (CDT) at baseline and follow-up. All analyses were adjusted for age, gender and years of education. RESULTS In the cross-sectional analysis, the present study found soluble IL-2 receptor (sIL-2R) to be associated only with the MMSE score at baseline in men. In the longitudinal analysis, none of our inflammatory biomarkers were associated with either depressive symptoms or cognitive decline. LIMITATIONS The present study consists of small number of participants and body mass index (BMI) scores were not obtained. CONCLUSIONS Our findings suggest that sIL-2R is associated with current cognitive function in men. None of our inflammatory markers predicted future depressive state or cognitive decline in our community-dwelling healthy older sample.

Association of saliva 3-methoxy-4-hydroxyphenylglycol levels and a later depressive state in older subjects living in a rural community: 3-year follow-up study.

The aim of the study was to examine the association of saliva levels of 3‐methoxy‐4‐hydroxyphenylglycol (sMHPG) with a later depressive state in older people living in a rural community.

Saliva levels of 3-methoxy-4-hydroxyphenylglycol and clinical efficacy of mirtazapine or selective serotonin reuptake inhibitors in patients with major depression

This study compared saliva levels of 3‐methoxy‐4‐hydroxyphenylglycol (sMHPG) in patients with major depressive disorder (MDD) to levels in healthy controls and explored whether sMHPG levels in patients with MDD were a predictive marker for antidepressant efficacy.

Relationship between saliva level of 3-methoxy-4-hydroxyphenylglycol and mental health in the elderly general population

Aims:  A large number of studies on the monoamine systems in Alzheimers disease (AD) have found abnormalities of the noradrenergic system in the brain, but there has been no report concerning the relationship between noradrenergic activity and cognitive function in elderly living in a community. The aim of the present study was to explore the relationship between saliva level of 3‐methoxy‐4‐hydroxyphenylglycol (sMHPG) and mental health in this population.