Publications by authors named "Hiroshi Kunugi"

338 Publications

Profiling of Cerebrospinal Fluid Lipids and Their Relationship with Plasma Lipids in Healthy Humans.

Metabolites 2021 Apr 24;11(5). Epub 2021 Apr 24.

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

Lipidomics provides an overview of lipid profiles in biological systems. Although blood is commonly used for lipid profiling, cerebrospinal fluid (CSF) is more suitable for exploring lipid homeostasis in brain diseases. However, whether an individual's background affects the CSF lipid profile remains unclear, and the association between CSF and plasma lipid profiles in heathy individuals has not yet been defined. Herein, lipidomics approaches were employed to analyze CSF and plasma samples obtained from 114 healthy Japanese subjects. Results showed that the global lipid profiles differed significantly between CSF and plasma, with only 13 of 114 lipids found to be significantly correlated between the two matrices. Additionally, the CSF total protein content was the primary factor associated with CSF lipids. In the CSF, the levels of major lipids, namely, phosphatidylcholines, sphingomyelins, and cholesterolesters, correlated with CSF total protein levels. These findings indicate that CSF lipidomics can be applied to explore changes in lipid homeostasis in patients with brain diseases.
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http://dx.doi.org/10.3390/metabo11050268DOI Listing
April 2021

Skeletal Muscle Damage in COVID-19: A Call for Action.

Medicina (Kaunas) 2021 Apr 12;57(4). Epub 2021 Apr 12.

Department of Psychiatry, School of Medicine, Teikyo University, Tokyo 173-8605, Japan.

Both laboratory investigations and body composition quantification measures (e.g., computed tomography, CT) portray muscle loss in symptomatic Coronavirus disease 2019 (COVID-19) patients. Muscle loss is associated with a poor prognosis of the disease. The exact mechanism of muscle damage in COVID-19 patients, as well as the long-term consequences of muscle injury in disease survivors, are unclear. The current review briefly summarizes the literature for mechanisms, assessment measures, and interventions relevant to skeletal muscle insult in COVID-19 patients. Muscle injury is likely to be attributed to the cytokine storm, disease severity, malnutrition, prolonged physical inactivity during intensive care unit (ICU) stays, mechanical ventilation, and myotoxic drugs (e.g., dexamethasone). It has been assessed by imaging and non-imaging techniques (e.g., CT and electromyography), physical performance tests (e.g., six-minute walk test), anthropometric measures (e.g., calf circumference), and biomarkers of muscle dystrophy (e.g., creatine kinase). Interventions directed toward minimizing muscle loss among COVID-19 patients are lacking. However, limited evidence shows that respiratory rehabilitation improves respiratory function, muscle strength, quality of life, and anxiety symptoms in recovering older COVID-19 patients. Neuromuscular electrical stimulation may restore muscle condition in ICU-admitted patients, albeit empirical evidence is needed. Given the contribution of malnutrition to disease severity and muscle damage, providing proper nutritional management for emaciated patients may be one of the key issues to achieve a better prognosis and prevent the after-effects of the disease. Considerable attention to longer-term consequences of muscle injury in recovering COVID-19 patients is necessary.
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http://dx.doi.org/10.3390/medicina57040372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069858PMC
April 2021

Association of Age, Antipsychotic Medication, and Symptom Severity in Schizophrenia With Proton Magnetic Resonance Spectroscopy Brain Glutamate Level: A Mega-analysis of Individual Participant-Level Data.

JAMA Psychiatry 2021 Apr 21. Epub 2021 Apr 21.

Department of Psychiatry, Columbia University, New York State Psychiatric Institute, New York.

Importance: Proton magnetic resonance spectroscopy (1H-MRS) studies indicate that altered brain glutamatergic function may be associated with the pathophysiology of schizophrenia and the response to antipsychotic treatment. However, the association of altered glutamatergic function with clinical and demographic factors is unclear.

Objective: To assess the associations of age, symptom severity, level of functioning, and antipsychotic treatment with brain glutamatergic metabolites.

Data Sources: The MEDLINE database was searched to identify journal articles published between January 1, 1980, and June 3, 2020, using the following search terms: MRS or magnetic resonance spectroscopy and (1) schizophrenia or (2) psychosis or (3) UHR or (4) ARMS or (5) ultra-high risk or (6) clinical high risk or (7) genetic high risk or (8) prodrome* or (9) schizoaffective. Authors of 114 1H-MRS studies measuring glutamate (Glu) levels in patients with schizophrenia were contacted between January 2014 and June 2020 and asked to provide individual participant data.

Study Selection: In total, 45 1H-MRS studies contributed data.

Data Extraction And Synthesis: Associations of Glu, Glu plus glutamine (Glx), or total creatine plus phosphocreatine levels with age, antipsychotic medication dose, symptom severity, and functioning were assessed using linear mixed models, with study as a random factor.

Main Outcomes And Measures: Glu, Glx, and Cr values in the medial frontal cortex (MFC) and medial temporal lobe (MTL).

Results: In total, 42 studies were included, with data for 1251 patients with schizophrenia (mean [SD] age, 30.3 [10.4] years) and 1197 healthy volunteers (mean [SD] age, 27.5 [8.8] years). The MFC Glu (F1,1211.9 = 4.311, P = .04) and Glx (F1,1079.2 = 5.287, P = .02) levels were lower in patients than in healthy volunteers, and although creatine levels appeared lower in patients, the difference was not significant (F1,1395.9 = 3.622, P = .06). In both patients and volunteers, the MFC Glu level was negatively associated with age (Glu to Cr ratio, F1,1522.4 = 47.533, P < .001; cerebrospinal fluid-corrected Glu, F1,1216.7 = 5.610, P = .02), showing a 0.2-unit reduction per decade. In patients, antipsychotic dose (in chlorpromazine equivalents) was negatively associated with MFC Glu (estimate, 0.10 reduction per 100 mg; SE, 0.03) and MFC Glx (estimate, -0.11; SE, 0.04) levels. The MFC Glu to Cr ratio was positively associated with total symptom severity (estimate, 0.01 per 10 points; SE, 0.005) and positive symptom severity (estimate, 0.04; SE, 0.02) and was negatively associated with level of global functioning (estimate, 0.04; SE, 0.01). In the MTL, the Glx to Cr ratio was positively associated with total symptom severity (estimate, 0.06; SE, 0.03), negative symptoms (estimate, 0.2; SE, 0.07), and worse Clinical Global Impression score (estimate, 0.2 per point; SE, 0.06). The MFC creatine level increased with age (estimate, 0.2; SE, 0.05) but was not associated with either symptom severity or antipsychotic medication dose.

Conclusions And Relevance: Findings from this mega-analysis suggest that lower brain Glu levels in patients with schizophrenia may be associated with antipsychotic medication exposure rather than with greater age-related decline. Higher brain Glu levels may act as a biomarker of illness severity in schizophrenia.
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http://dx.doi.org/10.1001/jamapsychiatry.2021.0380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060889PMC
April 2021

Hypoproteinemia predicts disease severity and mortality in COVID-19: a call for action.

Diagn Pathol 2021 Apr 13;16(1):31. Epub 2021 Apr 13.

Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.

Proteins represent the major building blocks of body tissues, and they regulate signaling involved in most cellular activities. Coronavirus disease 2019 (COVID-19) infection has been associated with high fatality, especially among older adults. The main cause of death is pulmonary tissue damage and multiple organ failure. The disease is associated with a hypercatabolic state that entails excessive protein loss. This review commentary sheds the light on hypoproteinemia in symptomatic/hospitalized COVID-19 with a special emphasis on its pathophysiology, screening, as well as its contribution to disease severity and adverse effects.
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http://dx.doi.org/10.1186/s13000-021-01092-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042835PMC
April 2021

The Arabic Version of the Cohen Perceived Stress Scale: Factorial Validity and Measurement Invariance.

Brain Sci 2021 Mar 26;11(4). Epub 2021 Mar 26.

National Center of Neurology and Psychiatry, Department of Mental Disorder Research, National Institute of Neuroscience, Tokyo 187-0031, Japan.

University students experience high levels of stress due to university transition, academic commitments, and financial matters. Higher stress perceptions along with limited coping resources endanger mental health for a considerable number of students and may ruin their performance. The current study evaluated the psychometric properties of the Cohen Perceived Stress Scale (10 items), PSS-10, in a sample of 379 female Emeriti students. Exploratory factor analysis resulted in two factors with eigenvalues of 3.88 and 1.19, which explained 60.6% of the variance. Confirmatory factor analysis revealed good model fits of two correlated factors (Comparative Fit Index (CFI) = 0.962, Tucker-Lewis Index (TLI) = 0.950, standardized root-mean-square residual (SRMR) = 0.0479, and root mean-square error of approximation (RMSEA) = 0.067). Internal consistency of the PSS-10 and its positive and negative subscales was acceptable (coefficient α = 0.67, 0.79, and 0.86, respectively). Multigroup analysis revealed that the PSS-10 holds invariance across different groups of age, marital status, and financial status (average monthly expenditure). Convergent and concurrent validity tests signify the importance of considering scores of subscales of the PSS-10 along with its total score.
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http://dx.doi.org/10.3390/brainsci11040419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066085PMC
March 2021

Approaches to Nutritional Screening in Patients with Coronavirus Disease 2019 (COVID-19).

Int J Environ Res Public Health 2021 03 9;18(5). Epub 2021 Mar 9.

National Center of Neurology and Psychiatry, Department of Mental Disorder Research, National Institute of Neuroscience, Tokyo 187-0031, Japan.

Malnutrition is common among severe patients with coronavirus disease 2019 (COVID-19), mainly elderly adults and patients with comorbidities. It is also associated with atypical presentation of the disease. Despite the possible contribution of malnutrition to the acquisition and severity of COVID-19, it is not clear which nutritional screening measures may best diagnose malnutrition in these patients at early stages. This is of crucial importance given the urgency and rapid progression of the disease in vulnerable groups. Accordingly, this review examines the available literature for different nutritional screening approaches implemented among COVID-19 patients, with a special focus on elderly adults. After a literature search, we selected and scrutinized 14 studies assessing malnutrition among COVID-19 patients. The Nutrition Risk Screening 2002 (NRS-2002) has demonstrated superior sensitivity to other traditional screening measures. The controlling nutritional status (CONUT) score, which comprises serum albumin level, cholesterol level, and lymphocytes count, as well as a combined CONUT-lactate dehydrogenase-C-reactive protein score expressed a predictive capacity even superior to that of NRS-2002 (0.81% and 0.92% vs. 0.79%) in midlife and elder COVID-19 patients. Therefore, simple measures based on routinely conducted laboratory investigations such as the CONUT score may be timely, cheap, and valuable alternatives for identifying COVID-19 patients with high nutritional risk. Mini Nutritional Assessment (MNA) was the only measure used to detect residual malnutrition and high malnutrition risk in remitting patients-MNA scores correlated with hypoalbuminemia, hypercytokinemia, and weight loss. Older males with severe inflammation, gastrointestinal symptoms, and pre-existing comorbidities (diabetes, obesity, or hypertension) are more prone to malnutrition and subsequently poor COVID-19 prognosis both during the acute phase and during convalescence. Thus, they are in need of frequent nutritional monitoring and support while detecting and treating malnutrition in the general public might be necessary to increase resilience against COVID-19.
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http://dx.doi.org/10.3390/ijerph18052772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967488PMC
March 2021

Cerebrospinal Fluid Inflammatory Cytokine Levels in Patients With Major Psychiatric Disorders: A Multiplex Immunoassay Study.

Front Pharmacol 2020 1;11:594394. Epub 2021 Feb 1.

Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.

Accumulating evidence suggests that neural inflammation plays an important role in psychiatric disorders. We aimed to identify inflammatory cytokines involved in the pathophysiology of such disorders by quantifying them in cerebrospinal fluid (CSF) samples from a large sample of patients with major psychiatric disorders and healthy controls. The subjects included 94 patients with schizophrenia, 68 with bipolar disorder, 104 with major depressive disorder, and 118 healthy controls, matched for age, sex, and ethnicity (Japanese). Lumbar puncture was performed to collect these CSF samples. A multiplex immunoassay was then performed to measure CSF cytokine levels using magnetic on-bead antibody conjugation for 19 inflammatory cytokines. CSF interferon-β level was significantly higher in total psychiatric patients than in healthy controls (corrected = 0.000029). In diagnostic group comparisons, CSF interferon-β level was significantly higher in patients with schizophrenia, or bipolar disorder (corrected = 0.000047 or 0.0034) than in healthy controls. We present novel evidence that CSF IFN-β level showed prominent statistical differences between psychiatric groups and healthy controls. This suggests IFN-β as the most important player among the 19 cytokines tested here in the inflammation-related pathophysiology of major psychiatric disorders.
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http://dx.doi.org/10.3389/fphar.2020.594394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941212PMC
February 2021

Propolis, Bee Honey, and Their Components Protect against Coronavirus Disease 2019 (COVID-19): A Review of In Silico, In Vitro, and Clinical Studies.

Molecules 2021 Feb 25;26(5). Epub 2021 Feb 25.

Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-0031, Japan.

Despite the virulence and high fatality of coronavirus disease 2019 (COVID-19), no specific antiviral treatment exists until the current moment. Natural agents with immune-promoting potentials such as bee products are being explored as possible treatments. Bee honey and propolis are rich in bioactive compounds that express strong antimicrobial, bactericidal, antiviral, anti-inflammatory, immunomodulatory, and antioxidant activities. This review examined the literature for the anti-COVID-19 effects of bee honey and propolis, with the aim of optimizing the use of these handy products as prophylactic or adjuvant treatments for people infected with severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). Molecular simulations show that flavonoids in propolis and honey (e.g., rutin, naringin, caffeic acid phenyl ester, luteolin, and artepillin C) may inhibit viral spike fusion in host cells, viral-host interactions that trigger the cytokine storm, and viral replication. Similar to the potent antiviral drug remdesivir, rutin, propolis ethanolic extract, and propolis liposomes inhibited non-structural proteins of SARS-CoV-2 in vitro and these compounds along with naringin inhibited SARS-CoV-2 infection in Vero E6 cells. Propolis extracts delivered by nanocarriers exhibit better antiviral effects against SARS-CoV-2 than ethanolic extracts. In line, hospitalized COVID-19 patients receiving green Brazilian propolis or a combination of honey and exhibited earlier viral clearance, symptom recovery, discharge from the hospital as well as less mortality than counterparts receiving standard care alone. Thus, the use of bee products as an adjuvant treatment for COVID-19 may produce beneficial effects. Implications for treatment outcomes and issues to be considered in future studies are discussed.
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http://dx.doi.org/10.3390/molecules26051232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956496PMC
February 2021

Childhood maltreatment history and attention bias variability in healthy adult women: role of inflammation and the BDNF Val66Met genotype.

Transl Psychiatry 2021 Feb 11;11(1):122. Epub 2021 Feb 11.

Department of Behavioral Medicine, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan.

Childhood maltreatment has been associated with greater attention bias to emotional information, but the findings are controversial. Recently, a novel index of attention bias, i.e., attention bias variability (ABV), has been developed to better capture trauma-related attentional dysfunction. However, ABV in relation to childhood trauma has not been studied. Here, we examined the association of childhood maltreatment history with attention bias/ABV in 128 healthy adult women. Different types of childhood maltreatment were assessed with the Childhood Trauma Questionnaire. Attention bias/ABV was measured by the dot-probe task. Possible mechanisms whereby childhood maltreatment affects attention bias/ABV were also explored, focusing on blood proinflammatory markers and the BDNF Val66Met polymorphism. We observed a significant positive correlation between childhood emotional abuse and ABV (P = 0.002). Serum high-sensitivity tumor necrosis factor-α levels were significantly positively correlated with ABV (P < 0.001), but not with childhood maltreatment. Jonckheere-Terpstra trend test showed a significant tendency toward greater ABV with increasing numbers of the BDNF Met alleles (P = 0.021). A two-way analysis of variance further revealed that the genotype-by-emotional abuse interaction for ABV was significant (P = 0.022); individuals with the Val/Met and Met/Met genotypes exhibited even greater ABV when childhood emotional abuse was present. These results indicate that childhood emotional abuse can have a long-term negative impact on emotional attention control. Increased inflammation may be involved in the mechanism of ABV, possibly independently of childhood maltreatment. The BDNF Met allele may dose-dependently increase ABV by interacting with childhood emotional abuse.
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http://dx.doi.org/10.1038/s41398-021-01247-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878504PMC
February 2021

Sirtuin 6 is a regulator of dendrite morphogenesis in rat hippocampal neurons.

Neurochem Int 2021 05 12;145:104959. Epub 2021 Jan 12.

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

Sirtuin 6 (SIRT6), a member of the Sirtuin family, acts as nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylase, mono-adenosine diphosphate (ADP)-ribosyltransferase, and fatty acid deacylase, and plays critical roles in inflammation, aging, glycolysis, and DNA repair. Accumulating evidence has suggested that SIRT6 is involved in brain functions such as neuronal differentiation, neurogenesis, and learning and memory. However, the precise molecular roles of SIRT6 during neuronal circuit formation are not yet well understood. In this study, we tried to elucidate molecular roles of SIRT6 on neurite development by using primary-cultured hippocampal neurons. We observed that SIRT6 was abundantly localized in the nucleus, and its expression was markedly increased during neurite outgrowth and synaptogenesis. By using shRNA-mediated SIRT6-knockdown, we show that both dendritic length and the number of dendrite branches were significantly reduced in the SIRT6-knockdown neurons. Microarray and subsequent gene ontology analysis revealed that reducing SIRT6 caused the downregulation of immediate early genes (IEGs) and alteration of several biological processes including MAPK (ERK1/2) signaling. We found that nuclear accumulation of phosphorylated ERK1/2 was significantly reduced in SIRT6-knockdown neurons. Overexpression of SIRT6 promoted dendritic length and branching, but the mutants lacking deacetylase activity had no significant effect on the dendritic morphology. Collectively, the presented findings reveal a role of SIRT6 in dendrite morphogenesis, and suggest that SIRT6 may act as an important regulator of ERK1/2 signaling pathway that mediates IEG expression, which leads to dendritic development.
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http://dx.doi.org/10.1016/j.neuint.2021.104959DOI Listing
May 2021

Small noncoding vault RNA modulates synapse formation by amplifying MAPK signaling.

J Cell Biol 2021 Feb;220(2)

Department of Peripheral Nervous System Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.

The small noncoding vault RNA (vtRNA) is a component of the vault complex, a ribonucleoprotein complex found in most eukaryotes. Emerging evidence suggests that vtRNAs may be involved in the regulation of a variety of cellular functions when unassociated with the vault complex. Here, we demonstrate a novel role for vtRNA in synaptogenesis. Using an in vitro synapse formation model, we show that murine vtRNA (mvtRNA) promotes synapse formation by modulating the MAPK signaling pathway. mvtRNA is transported to the distal region of neurites as part of the vault complex. Interestingly, mvtRNA is released from the vault complex in the neurite by a mitotic kinase Aurora-A-dependent phosphorylation of MVP, a major protein component of the vault complex. mvtRNA binds to and activates MEK1 and thereby enhances MEK1-mediated ERK activation in neurites. These results suggest the existence of a regulatory mechanism of the MAPK signaling pathway by vtRNAs as a new molecular basis for synapse formation.
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http://dx.doi.org/10.1083/jcb.201911078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809882PMC
February 2021

Performance on the Wechsler Adult Intelligence Scale (WAIS) in Japanese patients with bipolar and major depressive disorders in euthymic and depressed states.

Psychiatry Clin Neurosci 2021 Apr 10;75(4):128-137. Epub 2021 Feb 10.

Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.

Aim: This study aimed to examine the cognitive performance of patients with bipolar disorder (BD) stratified by illness phase compared to that of patients with major depressive disorder (MDD) and healthy controls.

Methods: Participants were 139 patients with BD (55 euthymic and 84 depressed), 311 patients with MDD (88 euthymic and 223 depressed), and 386 healthy controls who underwent the Wechsler Adult Intelligence Scale-Revised or the Third Edition. They were non-elderly Japanese individuals with normal estimated premorbid intelligence quotient (IQ; >90), group-matched for age, sex, and premorbid IQ.

Results: The depressed BD group showed significantly lower scores on verbal IQ, performance IQ, full-scale IQ, and three group indexes of perceptual organization, working memory, and processing speed when compared with healthy controls (all P < 0.001). All IQs and working memory index were also significantly lower than those of the depressed MDD group. The depressed MDD group scored significantly lower than controls in performance IQ (P < 0.001), full-scale IQ, and only in the index of processing speed (P < 0.001). The euthymic BD group scored significantly lower than controls in performance IQ (P = 0.004), whereas the euthymic MDD group scored significantly lower than controls only in processing speed (P = 0.030).

Conclusion: Patients with BD appear to have global and more intense cognitive impairments in depressed states compared with those with MDD whose impairments seem to be apparent only in processing speed in the Wechsler Adult Intelligence Scale. Attenuated impairments appear to exist in euthymic states of both patients.
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http://dx.doi.org/10.1111/pcn.13191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048446PMC
April 2021

Structural brain network differences in bipolar disorder using with similarity-based approach.

Acta Neuropsychiatr 2021 Jun 22;33(3):121-125. Epub 2020 Dec 22.

Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1, Ogawa-Higashi, Kodaira, Tokyo187-8502, Japan.

Objective: Previous studies have shown differences in the regional brain structure and function between patients with bipolar disorder (BD) and healthy subjects, but little is known about the structural connectivity between BD patients and healthy subjects. In this study, we evaluated the disease-related changes in regional structural connectivity derived from gray matter magnetic resonance imaging (MRI) scans. Methods: The subjects were 73 patients with BD and 80 healthy volunteers who underwent 3-Tesla MRI. Network metrics, such as the small world properties, were computed. We also performed rendering of the network metric images such as the degree, betweenness centrality, and clustering coefficient, on individual brain image. Then, we estimated the differences between them, and evaluate the relationships between the clinical symptoms and the network metrics in the patients with BD. Results: BD patients showed a lower clustering coefficient in the right parietal region and left occipital region, compared with healthy subjects. A weak negative correlation between Young mania rating scale and clustering coefficient was found in left anterior cingulate cortex. Conclusions: We found differences in gray matter structural connectivity between BD patients and healthy subjects by a similarity-based approach. These points may provide objective biological information as an adjunct to the clinical diagnosis of BD.
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http://dx.doi.org/10.1017/neu.2020.45DOI Listing
June 2021

Intermittent Fasting, Dietary Modifications, and Exercise for the Control of Gestational Diabetes and Maternal Mood Dysregulation: A Review and a Case Report.

Int J Environ Res Public Health 2020 12 15;17(24). Epub 2020 Dec 15.

Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-0031, Japan.

Gestational diabetes mellitus (GDM) is a common pregnancy-related condition afflicting 5-36% of pregnancies. It is associated with many morbid maternal and fetal outcomes. Mood dysregulations (MDs, e.g., depression, distress, and anxiety) are common among women with GDM, and they exacerbate its prognosis and hinder its treatment. Hence, in addition to early detection and proper management of GDM, treating the associated MDs is crucial. Maternal hyperglycemia and MDs result from a complex network of genetic, behavioral, and environmental factors. This review briefly explores mechanisms that underlie GDM and prenatal MDs. It also describes the effect of exercise, dietary modification, and intermittent fasting (IF) on metabolic and affective dysfunctions exemplified by a case report. In this patient, interventions such as IF considerably reduced maternal body weight, plasma glucose, and psychological distress without any adverse effects. Thus, IF is one measure that can control GDM and maternal MDs; however, more investigations are warranted.
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http://dx.doi.org/10.3390/ijerph17249379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765295PMC
December 2020

Association of CRP genetic variation with symptomatology, cognitive function, and circulating proinflammatory markers in civilian women with PTSD.

J Affect Disord 2021 01 1;279:640-649. Epub 2020 Nov 1.

Department of Behavioral Medicine, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan.

Background: Posttraumatic stress disorder (PTSD) has been associated with increased inflammation. C-reactive protein (CRP) is a marker of systemic inflammation, and recently, single nucleotide polymorphisms (SNPs) in the CRP gene have been associated with increased blood CRP protein levels and illness severity in PTSD patients. However, the mechanism by which the CRP SNPs are involved in PTSD remains unclear. Here we investigated the association of CRP genetic variation with blood proinflammatory protein levels, symptomatology, and cognitive function, and further explored the moderating effect of childhood maltreatment history, in adult patients with PTSD.

Methods: Fifty-seven Japanese civilian women with PTSD and 73 healthy control women were enrolled. Three SNPs in the CRP gene, namely rs2794520, rs1130864, and rs3093059, were genotyped, and analyses focused on rs2794520 (T/C). Serum levels of high-sensitivity CRP (hsCRP), high-sensitivity tumor necrosis factor-α (hsTNF-α), and interleukin-6 were measured. PTSD symptoms were evaluated by the Posttraumatic Diagnostic Scale. Cognitive function was assessed by the Repeatable Battery for the Assessment of Neuropsychological Status. Childhood maltreatment history was assessed by the Childhood Trauma Questionnaire.

Results: Patients with the rs2794520 CC/CT genotype, compared to those with the TT genotype, showed significantly higher levels of hsCRP (p=0.009) and hsTNF-α (p=0.001), more severe PTSD symptoms (p=0.036), and poorer cognitive function (p=0.018). A two-way analysis of variance revealed a significant genotype-by-maltreatment interaction for more severe PTSD avoidance symptom (p=0.012).

Limitations: The relatively small sample size limited our findings.

Conclusions: These findings may provide an insight into the etiology of PTSD from the inflammatory perspective.
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http://dx.doi.org/10.1016/j.jad.2020.10.045DOI Listing
January 2021

Apitherapy for Parkinson's Disease: A Focus on the Effects of Propolis and Royal Jelly.

Oxid Med Cell Longev 2020 17;2020:1727142. Epub 2020 Oct 17.

Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.

The vast increase of world's aging populations is associated with increased risk of age-related neurodegenerative diseases such as Parkinson's disease (PD). PD is a widespread disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra, which encompasses a wide range of debilitating motor, emotional, cognitive, and physical symptoms. PD threatens the quality of life of millions of patients and their families. Additionally, public welfare and healthcare systems are burdened with its high cost of care. Available treatments provide only a symptomatic relief and produce a trail of noxious side effects, which increase noncompliance. Hence, researchers have recently focused on the use of nutraceuticals as safe adjunctive treatments of PD to limit its progress and associated damages in affected groups. Propolis is a common product of the beehive, which possesses a large number of therapeutic properties. Royal jelly (RJ) is a bee product that is fed to bee queens during their entire life, and it contributes to their high physical fitness, fertility, and long lifespan. Evidence suggests that propolis and RJ can promote health by preventing the occurrence of age-related debilitating diseases. Therefore, they have been used to treat various serious disorders such as diabetes mellitus, cardiovascular diseases, and cancer. Some evolving studies used these bee products to treat PD in animal models. However, a clear understanding of the collective effect of propolis and RJ as well as their mechanism of action in PD is lacking. This review evaluates the available literature for the effects of propolis and RJ on PD. Whenever possible, it elaborates on the underlying mechanisms through which they function in this disorder and offers insights for fruitful use of bee products in future clinical trials.
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http://dx.doi.org/10.1155/2020/1727142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586183PMC
October 2020

Royal Jelly as an Intelligent Anti-Aging Agent-A Focus on Cognitive Aging and Alzheimer's Disease: A Review.

Antioxidants (Basel) 2020 Sep 29;9(10). Epub 2020 Sep 29.

Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-0031, Japan.

The astronomical increase of the world's aged population is associated with the increased prevalence of neurodegenerative diseases, heightened disability, and extremely high costs of care. Alzheimer's Disease (AD) is a widespread, age-related, multifactorial neurodegenerative disease that has enormous social and financial drawbacks worldwide. The unsatisfactory outcomes of available AD pharmacotherapy necessitate the search for alternative natural resources that can target various the underlying mechanisms of AD pathology and reduce disease occurrence and/or progression. Royal jelly (RJ) is the main food of bee queens; it contributes to their fertility, long lifespan, and memory performance. It represents a potent nutraceutical with various pharmacological properties, and has been used in a number of preclinical studies to target AD and age-related cognitive deterioration. To understand the mechanisms through which RJ affects cognitive performance both in natural aging and AD, we reviewed the literature, elaborating on the metabolic, molecular, and cellular mechanisms that mediate its anti-AD effects. Preclinical findings revealed that RJ acts as a multidomain cognitive enhancer that can restore cognitive performance in aged and AD models. It promotes brain cell survival and function by targeting multiple adversities in the neuronal microenvironment such as inflammation, oxidative stress, mitochondrial alterations, impaired proteostasis, amyloid-β toxicity, Ca excitotoxicity, and bioenergetic challenges. Human trials using RJ in AD are limited in quantity and quality. Here, the limitations of RJ-based treatment strategies are discussed, and directions for future studies examining the effect of RJ in cognitively impaired subjects are noted.
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http://dx.doi.org/10.3390/antiox9100937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601550PMC
September 2020

Apitherapy for Age-Related Skeletal Muscle Dysfunction (Sarcopenia): A Review on the Effects of Royal Jelly, Propolis, and Bee Pollen.

Foods 2020 Sep 25;9(10). Epub 2020 Sep 25.

Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-0031, Japan.

The global pandemic of sarcopenia, skeletal muscle loss and weakness, which prevails in up to 50% of older adults is increasing worldwide due to the expansion of aging populations. It is now striking young and midlife adults as well because of sedentary lifestyle and increased intake of unhealthy food (e.g., western diet). The lockdown measures and economic turndown associated with the current outbreak of Coronavirus Disease 2019 (COVID-19) are likely to increase the prevalence of sarcopenia by promoting sedentarism and unhealthy patterns of eating. Sarcopenia has multiple detrimental effects including falls, hospitalization, disability, and institutionalization. Although a few pharmacological agents (e.g., bimagrumab, sarconeos, and exercise mimetics) are being explored in different stages of trials, not a single drug has been approved for sarcopenia treatment. Hence, research has focused on testing the effect of nutraceuticals, such as bee products, as safe treatments to prevent and/or treat sarcopenia. Royal jelly, propolis, and bee pollen are common bee products that are rich in highly potent antioxidants such as flavonoids, phenols, and amino acids. These products, in order, stimulate larval development into queen bees, promote defenses of the bee hive against microbial and environmental threats, and increase royal jelly production by nurse bees. Thanks to their versatile pharmacological activities (e.g., anti-aging, anti-inflammatory, anticarcinogenic, antimicrobial, etc.), these products have been used to treat multiple chronic conditions that predispose to muscle wasting such as hypertension, diabetes mellitus, cardiovascular disorder, and cancer, to name a few. They were also used in some evolving studies to treat sarcopenia in laboratory animals and, to a limited degree, in humans. However, a collective understanding of the effect and mechanism of action of these products in skeletal muscle is not well-developed. Therefore, this review examines the literature for possible effects of royal jelly, bee pollen, and propolis on skeletal muscle in aged experimental models, muscle cell cultures, and humans. Collectively, data from reviewed studies denote varying levels of positive effects of bee products on muscle mass, strength, and function. The likely underlying mechanisms include amelioration of inflammation and oxidative damages, promotion of metabolic regulation, enhancement of satellite stem cell responsiveness, improvement of muscular blood supply, inhibition of catabolic genes, and promotion of peripheral neuronal regeneration. This review offers suggestions for other mechanisms to be explored and provides guidance for future trials investigating the effects of bee products among people with sarcopenia.
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http://dx.doi.org/10.3390/foods9101362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601109PMC
September 2020

Corrigendum: Correlation Between the Wechsler Adult Intelligence Scale- Edition Metrics and Brain Structure in Healthy Individuals: A Whole-Brain Magnetic Resonance Imaging Study.

Front Hum Neurosci 2020 21;14:291. Epub 2020 Aug 21.

Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.

[This corrects the article DOI: 10.3389/fnhum.2020.00211.].
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http://dx.doi.org/10.3389/fnhum.2020.00291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473456PMC
August 2020

Association between obesity and white matter microstructure impairments in patients with schizophrenia: A whole-brain magnetic resonance imaging study.

Schizophr Res 2020 Aug 5. Epub 2020 Aug 5.

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; Department of Psychiatry, Teikyo University School of Medicine, Tokyo 173-8605, Japan. Electronic address:

Aim: We aimed to examine the possible association of obesity (body mass index [BMI] ≥ 30) with symptoms, psychotropic medication, and whole-brain structure in patients with schizophrenia.

Methods: Participants were 65 patients diagnosed with schizophrenia (mean age: 37.2 ± 11.3 years, 32 females). All participants were Japanese and right-handed. Symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) and Pittsburgh Sleep Quality Index (PSQI). Voxel based morphometry (VBM) and diffusion tensor imaging (DTI) were performed to analyze the association of obesity with gray and white matter structures, respectively.

Results: There was no significant difference in PANSS scores between obese and non-obese patients, while the PSQI score was significantly higher in the former than in the latter (p < 0.05). The daily dose of typical antipsychotics was significantly higher in obese patients than in non-obese patients (p < 0.001). In VBM, there was no significant difference in gray matter volume between obese and non-obese patients. In DTI, fractional anisotropy values in the corpus callosum, corona radiata, corticospinal tract, superior longitudinal fasciculus, and posterior thalamic radiations were significantly lower in obese patients than in non-obese patients (corrected p < 0.05). Axial diffusivity was significantly lower while radial and mean diffusivities values were significantly higher in obese patients than in non-obese patients (corrected p < 0.05) in similar but more restricted brain regions.

Conclusion: Our results suggest that obesity is related to sleep disturbances, daily dose of typical antipsychotics, and regional white matter microstructure impairments in patients with schizophrenia.
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http://dx.doi.org/10.1016/j.schres.2020.07.009DOI Listing
August 2020

Increased matrix metalloproteinases in cerebrospinal fluids of patients with major depressive disorder and schizophrenia.

Int J Neuropsychopharmacol 2020 Jul 16. Epub 2020 Jul 16.

Division of Psychiatry and Neuroscience, Institute for Clinical Research, National Hospital Organization (NHO) Kure Medical Center and Chugoku Cancer Center, Kure, Hiroshima, Japan.

Background: Chronic inflammation of the brain has a pivotal role in the pathophysiology of major depressive disorder (MDD) and schizophrenia (SCZ). Matrix metalloproteinases (MMPs) are extracellular proteases involved in pro-inflammatory processes and interact with IL-6, which is increased in the cerebrospinal fluid (CSF) of patients with MDD and SCZ. However, MMPs in the CSF in patients with MDD and SCZ remains unclear. Therefore, we compared MMPs in the CSF of patients with MDD and SCZ to those of healthy controls (HC).

Methods: Japanese patients were diagnosed with DSM-IV-TR and clinical symptoms were assessed with the Hamilton Rating Scale for Depression for MDD and the Positive and Negative Syndrome Scale for SCZ. CSF was obtained from MDD (n=90), SCZ (n=86) and from age- and sex-matched HC (n=106). The levels of MMPs in CSF were measured with multiplex bead-based immunoassay.

Results: The levels of MMP-2 in CSF were higher in both MDD and SCZ than HC and were positively correlated with clinical symptomatic scores in MDD, but not in SCZ. Regardless of diagnosis, the levels of MMP-2, -7 and -10 were positively correlated with each other, and the levels of MMP-7 and -10 were higher in MDD, but not in SCZ, compared to HC.

Conclusion: Increased CSF levels of MMP-2 in MDD and SCZ may be associated with brain inflammation. State-dependent alteration of MMP-2 and activation of cascades involving MMP-2, -7, and -10 appeared to have a role in the pathophysiology of MDD.
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http://dx.doi.org/10.1093/ijnp/pyaa049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745248PMC
July 2020

Correlation Between the Wechsler Adult Intelligence Scale- 3 Edition Metrics and Brain Structure in Healthy Individuals: A Whole-Brain Magnetic Resonance Imaging Study.

Front Hum Neurosci 2020 3;14:211. Epub 2020 Jun 3.

Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.

Background: The Wechsler Adult Intelligence Scale, 3 edition (WAIS-III) is widely used to evaluate the intelligence quotient (IQ). We aimed to investigate the correlation between the WAIS-III metrics and whole-brain structures using magnetic resonance imaging.

Methods: The participants were 266 healthy, right-handed individuals (age: 45.6 ± 12.9 years, 98 males and 168 females). IQs were evaluated using the WAIS-III and Japanese Adult Reading Test (JART). Voxel-based morphometry and diffusion tensor imaging were performed to analyze the correlation of the WAIS-III metrics and JART score with the gray matter volume and white matter integrity, respectively.

Results: The verbal IQ significantly and positively correlated with the left gyrus rectus and anterior cingulate gyrus, left posterior insula and planum polare, and left superior and middle frontal gyri volumes ( < 0.05, corrected). The verbal comprehension group index significantly and positively correlated with the left superior and middle frontal gyri, left gyrus rectus and anterior cingulate gyrus, and left middle frontal gyrus volumes, while the processing speed group index significantly and positively correlated with the bilateral various regional white matter fractional anisotropy values ( < 0.05, corrected). In contrast, the JART score showed no correlation with any brain structure.

Conclusion: These results suggested the neurostructural bases of the WAIS-III IQs and group indices in the brain of healthy individuals.
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http://dx.doi.org/10.3389/fnhum.2020.00211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283913PMC
June 2020

AUTS2 Regulation of Synapses for Proper Synaptic Inputs and Social Communication.

iScience 2020 Jun 18;23(6):101183. Epub 2020 May 18.

Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, Tokyo 187-8502, Japan. Electronic address:

Impairments in synapse development are thought to cause numerous psychiatric disorders. Autism susceptibility candidate 2 (AUTS2) gene has been associated with various psychiatric disorders, such as autism and intellectual disabilities. Although roles for AUTS2 in neuronal migration and neuritogenesis have been reported, its involvement in synapse regulation remains unclear. In this study, we found that excitatory synapses were specifically increased in the Auts2-deficient primary cultured neurons as well as Auts2 mutant forebrains. Electrophysiological recordings and immunostaining showed increases in excitatory synaptic inputs as well as c-fos expression in Auts2 mutant brains, suggesting that an altered balance of excitatory and inhibitory inputs enhances brain excitability. Auts2 mutant mice exhibited autistic-like behaviors including impairments in social interaction and altered vocal communication. Together, these findings suggest that AUTS2 regulates excitatory synapse number to coordinate E/I balance in the brain, whose impairment may underlie the pathology of psychiatric disorders in individuals with AUTS2 mutations.
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http://dx.doi.org/10.1016/j.isci.2020.101183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267731PMC
June 2020

Cerebrospinal fluid neuroplasticity-associated protein levels in patients with psychiatric disorders: a multiplex immunoassay study.

Transl Psychiatry 2020 05 21;10(1):161. Epub 2020 May 21.

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.

To examine the role of neuroplasticity in the pathology of psychiatric disorders, we measured cerebrospinal fluid (CSF) neuroplasticity-associated protein levels. Participants were 94 patients with schizophrenia, 68 with bipolar disorder (BD), 104 with major depressive disorder (MDD), and 118 healthy controls, matched for age, sex, and ethnicity (Japanese). A multiplex immunoassay (22-plex assay) was performed to measure CSF neuroplasticity-associated protein levels. Among 22 proteins, 11 were successfully measured in the assay. CSF amyloid precursor protein (APP) and glial cell-derived neurotrophic factor (GDNF) levels were significantly lower in patients with schizophrenia, and CSF APP and neural cell adhesion molecule (NCAM)-1 levels were significantly lower in patients with BD, than in healthy controls (all p < 0.05). Positive and Negative Syndrome Scale total, positive, and general scores were significantly and positively correlated with CSF hepatocyte growth factor (HGF) (p < 0.01) and S100 calcium-binding protein B (S100B) (p < 0.05) levels in patients with schizophrenia. Young mania-rating scale score was significantly and positively correlated with CSF S100B level in patients with BD (p < 0.05). Hamilton Depression Rating Scale, core, sleep, activity, somatic anxiety, and delusion subscale scores were significantly and positively correlated with CSF HGF level, while sleep subscale score was positively correlated with CSF S100B and VEGF receptor 2 levels in patients with MDD (p < 0.05). Our results suggest that CSF APP, GDNF, and NCAM-1 levels are associated with psychiatric disorders, and that CSF HGF, S100B, and VEGF receptor 2 levels are related to psychiatric symptoms.
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http://dx.doi.org/10.1038/s41398-020-0843-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242469PMC
May 2020

Increased apolipoprotein E and decreased TNF-α in the cerebrospinal fluid of nondemented APOE-ε4 carriers.

Neuropsychopharmacol Rep 2020 06 19;40(2):201-205. Epub 2020 May 19.

Department of Mental Disorder Research, National Center of Neurology and Psychiatry, National Institute of Neuroscience, Kodaira, Japan.

Aim: The ε4 allele of apolipoprotein E gene (APOE) is a well-known risk factor of late-onset Alzheimer's disease. However, little is known why this variant confers a risk for Alzheimer's disease. The aim of this study was to examine the influence of the APOE genotype on cerebrospinal fluid (CSF) protein levels.

Methods: The present study performed a secondary analysis on our previously generated database to compare the CSF levels of 1128 proteins between APOE-ε4 carriers (28 subjects) and noncarriers (104 subjects). All subjects were physically healthy Japanese individuals without dementia.

Results: CSF levels of apoE2, apoE3, and apoE4 were significantly higher (all nominal P < 10 × 10 , false discovery rate < 0.001) and those of tumor necrosis factor-α (TNF-α) were significantly lower (nominal P = 1.39 × 10 , false discovery rate < 0.001) in APOE-ε4 carriers than in noncarriers. No significant correlation was observed between the CSF levels of TNF-α and any of the apoE proteins.

Conclusions: Our findings indicate the possible roles of apoE and TNF-α in the pathogenesis of APOE-ε4-associated Alzheimer's disease.
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http://dx.doi.org/10.1002/npr2.12110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722685PMC
June 2020

Possible Long-Term Effects of Childhood Maltreatment on Cognitive Function in Adult Women With Posttraumatic Stress Disorder.

Front Psychiatry 2020 24;11:344. Epub 2020 Apr 24.

Department of Behavioral Medicine, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan.

Accumulated evidence shows that individuals with posttraumatic stress disorder (PTSD) have compromised cognitive function. PTSD is associated with childhood maltreatment, which also can negatively affect cognitive function. It is therefore possible that cognitive dysfunction in adult patients with PTSD can be due at least partly to childhood maltreatment, although little is documented on this issue. Here we aimed to examine the possible effect of childhood maltreatment on cognitive function in adult patients with PTSD. A total of 50 women with DSM-IV PTSD and 94 healthy control women were enrolled. Most of the patients developed PTSD after experiencing interpersonal violence during adulthood. History of childhood maltreatment was assessed using the Childhood Trauma Questionnaire (CTQ). Cognitive functions were assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Compared to controls, patients reported significantly more experiences of all types of childhood maltreatment as assessed by the CTQ and showed significantly poorer performance on immediate memory, language, attention, and the total score of RBANS. In patients, sexual abuse scores were significantly negatively correlated with RBANS language ( < 0.001) and total score ( = 0.005). Further analyses revealed that PTSD patients with childhood sexual abuse had even poorer cognitive function than those without the abuse. In controls, no significant correlation was found between CTQ and RBANS scores. These results suggest that childhood maltreatment, specifically sexual abuse, may lead to persistent cognitive impairment in individuals with PTSD. Our findings might underscore the importance of early detection and intervention of childhood maltreatment, which will be achieved by careful observation of, and listening to, maltreated children in education and welfare scenes as well as clinical settings.
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http://dx.doi.org/10.3389/fpsyt.2020.00344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212372PMC
April 2020

Lauric acid promotes neuronal maturation mediated by astrocytes in primary cortical cultures.

Heliyon 2020 May 11;6(5):e03892. Epub 2020 May 11.

Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan.

Previous studies have suggested the potential efficacy of middle chain fatty acids (MCFAs) in the treatment of mood disorders and cognitive dysfunction. MCFAs are metabolized to ketone bodies in astrocytes; however, their effects on neuronal development including neurotrophic factor level are not well-understood. In the present study, we examined the effect of MCFAs on the mRNA expression of growth factors and cytokines in primary cultures of cortical astrocytes. The effect of MCFAs on neuron-astrocyte interaction in neuronal maturation was also determined using co-culture and astrocyte-conditioned medium. Lauric acid (LA) typically increased the mRNA expression of glial-derived neurotrophic factor (), interleukin-6 (), and C-C motif chemokine 2 () in astrocytes. LA-induced phosphorylation of extracellular signal-regulated kinase contributed to these changes. In primary cultures of cortical neurons containing astrocytes, LA enhanced the presynaptic protein levels. Astrocyte-conditioned medium after LA treatment also enhanced the presynaptic protein levels in the cortical neuron cultures. These results suggest that LA increase the mRNA expression of GDNF and cytokines in astrocytes, and thereby, enhances the presynaptic maturation.
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http://dx.doi.org/10.1016/j.heliyon.2020.e03892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218271PMC
May 2020

Characterization of Postprandial Effects on CSF Metabolomics: A Pilot Study with Parallel Comparison to Plasma.

Metabolites 2020 May 6;10(5). Epub 2020 May 6.

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

Cerebrospinal fluid (CSF) metabolites reflect biochemical diffusion/export from the brain and possibly serve as biomarkers related to brain disease severity, pathophysiology, and therapeutic efficacy/toxicity. Metabolomic studies using blood matrices have demonstrated interindividual and preanalytical variation of blood metabolites, whereas those of CSF metabolites remain unclear. In this study, we aimed to delineate the postprandial effects on CSF metabolites because fasting of patients with brain-related disorders is challenging. We collected pre- and postprandial (1.5, 3, and 6 h) plasma and CSF from nine healthy subjects. Using a mass-spectrometry-based global metabolomics approach, 150 and 130 hydrophilic metabolites and 263 and 340 lipids were detected in CSF and plasma, respectively. Principal component analysis of CSF hydrophilic metabolites and lipids primarily classified individual subjects at any time point, suggesting that the postprandial effects had a lower impact than interindividual variations on CSF metabolites. Individually, less than 10% of the CSF metabolites were putatively altered by postprandial effects (with either significant differences or over 2-fold changes, but not both) at any time point. Thus, global CSF metabolite levels are not directly associated with food intake, and except for several putatively altered CSF metabolites, postprandial effects are not a major concern when applying CSF metabolomics to screen biomarkers.
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http://dx.doi.org/10.3390/metabo10050185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281358PMC
May 2020

Lower cerebrospinal fluid CRH concentration in chronic schizophrenia with negative symptoms.

J Psychiatr Res 2020 08 16;127:13-19. Epub 2020 Apr 16.

Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, 187-8502, Japan. Electronic address:

Some patients with schizophrenia have impaired hypothalamic-pituitary-adrenal axis function. However, there is a dearth of studies focusing on corticotropin-releasing hormone (CRH) levels in the brains of schizophrenia patients, which motivated us to examine whether cerebrospinal fluid (CSF) CRH concentrations are altered in these patients. We also examined the possible correlation of CSF CRH level with clinical variables such as schizophrenia symptoms and antipsychotic medication. The study population comprised 20 patients with a diagnosis of schizophrenia according to DSM-5 criteria and 25 healthy controls, who underwent lumbar puncture. Most of the patients were treated with antipsychotic drugs and their doses were converted to chlorpromazine (CP) equivalent values. CSF CRH concentrations were measured by an enzyme immunoassay. Symptom severity was assessed using the Positive and Negative Syndrome Scale (PANSS). There was a significantly lower CSF CRH concentration in the patients than in the controls (Mann-Whitney U test: p = 0.014). A significantly negative correlation of CSF CRH levels with PANSS negative scores was found in the patients (Spearman's: ρ = -0.58, p = 0.007). However, CSF CRH concentrations were not significantly correlated with the PANSS total (ρ = -0.035, p = 0.89), positive (ρ = 0.25, p = 0.30), or general psychopathology (ρ = 0.13, p = 0.59) scores. No significant correlation was found with CP equivalent values (ρ = 0.00, p = 1.00). In conclusion, we found that the patients with schizophrenia had lower CSF CRH concentrations compared to the controls and that the lower CSF CRH was associated with negative symptoms of the illness. Further studies in a larger sample and in drug-free patients are warranted.
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http://dx.doi.org/10.1016/j.jpsychires.2020.03.010DOI Listing
August 2020

Possible associations between plasma fibroblast growth factor 21 levels and cognition in bipolar disorder.

Neuropsychopharmacol Rep 2020 06 8;40(2):175-181. Epub 2020 Apr 8.

Department of Mental Disorder Research, National Institute of Neuroscience, National Centre of Neurology and Psychiatry (NCNP), Tokyo, Japan.

Bipolar disorder (BD) is a mental disorder characterized by extreme changes in mood polarity. It is also characterized by cognitive and metabolic dysfunctions. Fibroblast growth factor 21 (FGF21) is an endocrine protein that has a multifaceted function such as glucose and lipid regulation in the periphery, and neuroprotection and induction of synaptic plasticity in the central nervous system. Previous studies reported inconsistent results concerning peripheral FGF21 levels in patients with BD. In this study, we compared plasma FGF21 levels between 26 patients with BD and 51 healthy controls using a human FGF21 ELISA Kit. There was no significant difference in plasma FGF21 levels between the patients and controls. We found significant positive correlations between plasma FGF21 levels and some cognitive parameters (word association and motor speed). If our results are replicated that higher peripheral FGF21 may be associated with better cognitive performance in patients with BD.
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http://dx.doi.org/10.1002/npr2.12102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722655PMC
June 2020