Supplementation with Matured Hop Bitter Acids Improves Cognitive Performance and Mood State in Healthy Older Adults with Subjective Cognitive Decline.

BACKGROUND: Prevention of age-related cognitive decline and depression is becoming urgent because of rapid growing aging populations. Effects of vagal nerve activation on brain function by food ingredients are inadequately investigated; matured hop bitter acid (MHBA) administration reportedly improves cognitive function and depression via vagal nerve activation in model mice. OBJECTIVE: We investigated the effects of MHBA supplementation on cognitive function and mood state in healthy older adults with perceived subjective cognitive decline. METHODS: Using a randomized double-blind placebo-controlled trial design, 100 subjects (aged 45-69 years) were randomly assigned into placebo (n = 50) and MHBA (n = 50) groups, and received placebo or MHBA capsules daily for 12 weeks. RESULTS: Symbol Digit Modalities Test (SDMT) score assessing divided attention at week 12 was significantly higher (p = 0.045) and ß-endorphin at week 12 was significantly lower (p = 0.043) in the subjects receiving MHBA. Transthyretin in serum, a putative mild cognitive impairment marker, was significantly higher at week 12 in the MHBA group than in the placebo group (p = 0.048). Subgroup analysis classified by the subjective cognitive decline questionnaire revealed that in addition to improved SDMT scores, memory retrieval assessed using the standard verbal paired-associate learning tests and the Ray Verbal Learning Test at week 12 had significantly improved in the subgroup with perceived subjective cognitive decline and without requirement for medical assistance in the MHBA group compared with that in the placebo group. CONCLUSION: This study suggested that MHBA intake improves cognitive function, attention, and mood state in older adults.

Use of skin advanced glycation end product levels measured using a simple noninvasive method as a biological marker for the diagnosis of neuropsychiatric diseases.

OBJECTIVES: The accumulation of advanced glycation end products (AGEs) may be involved in the pathophysiology of several neuropsychiatric diseases. In this study, the skin AGEs level of several neuropsychiatric diseases was assessed with a simple noninvasive method. Moreover, whether skin AGE level can be used as a biomarker for the diagnosis of these diseases was evaluated. METHODS: A total of 27 patients with schizophrenia, 26 with major depressive disorder, and 10 with major neurocognitive disorders (MNDs), such as Alzheimer's disease or dementia with Lewy body, as well as 26 healthy controls were enrolled in this study. The skin AGE levels of the patients were assessed with an AGE scanner, a fluorometric method used to assay skin AGE levels. RESULTS: One-way analysis of covariance was performed after adjusting for significant covariates, including age. Although the group with MNDs had higher skin AGE levels than the other groups, the main effect of diagnosis did not significantly affect the skin AGE levels of the groups. CONCLUSIONS: Skin AGE levels in neuropsychiatric diseases with mild symptoms did not significantly differ. Further large-scale studies using a simple noninvasive method for the early detection and treatment of MNDs must be conducted.

Skin advanced glycation end products as biomarkers of photosensitivity in schizophrenia.

OBJECTIVES: Photosensitivity to ultraviolet A (UVA) radiation from sunlight is an important side effect of treatment with antipsychotic agents. However, the pathophysiology of drug-induced photosensitivity remains unclear. Recent studies demonstrated the accumulation of advanced glycation end products (AGEs), annotated as carbonyl stress, to be associated with the pathophysiology of schizophrenia. In this study, we investigated the relationship among skin AGE levels, minimal response dose (MRD) with UVA for photosensitivity, and the daily dose of antipsychotic agents in patients with schizophrenia and healthy controls. METHODS: We enrolled 14 patients with schizophrenia and 14 healthy controls. Measurement of skin AGE levels was conducted with AGE scanner, a fluorometric method for assaying skin AGE levels. Measurement of MRD was conducted with UV irradiation device. RESULTS: Skin AGE levels and MRD at 24, 48, and 72 hr in patients with schizophrenia showed a higher tendency for photosensitivity than in the controls, but the difference was statistically insignificant. Multiple linear regression analysis using skin AGE levels failed to show any influence of independent variables. MRD did not affect skin AGE levels. CONCLUSIONS: Photosensitivity to UVA in patients with schizophrenia receiving treatment with antipsychotic agents might not be affected by skin AGE levels.

Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect.

Genome-wide association studies (GWASs) have identified >100 susceptibility loci for schizophrenia (SCZ) and demonstrated that SCZ is a polygenic disorder determined by numerous genetic variants but with small effect size. We conducted a GWAS in the Japanese (JPN) population (a) to detect novel SCZ-susceptibility genes and (b) to examine the shared genetic risk of SCZ across (East Asian [EAS] and European [EUR]) populations and/or that of trans-diseases (SCZ, bipolar disorder [BD], and major depressive disorder [MDD]) within EAS and between EAS and EUR (trans-diseases/populations). Among the discovery GWAS subjects (JPN-SCZ GWAS: 1940 SCZ cases and 7408 controls) and replication dataset (4071 SCZ cases and 54479 controls), both comprising JPN populations, 3 novel susceptibility loci for SCZ were identified: SPHKAP (Pbest = 4.1 × 10-10), SLC38A3 (Pbest = 5.7 × 10-10), and CABP1-ACADS (Pbest = 9.8 × 10-9). Subsequent meta-analysis between our samples and those of the Psychiatric GWAS Consortium (PGC; EUR samples) and another study detected 12 additional susceptibility loci. Polygenic risk score (PRS) prediction revealed a shared genetic risk of SCZ across populations (Pbest = 4.0 × 10-11) and between SCZ and BD in the JPN population (P ~ 10-40); however, a lower variance-explained was noted between JPN-SCZ GWAS and PGC-BD or MDD within/across populations. Genetic correlation analysis supported the PRS results; the genetic correlation between JPN-SCZ and PGC-SCZ was ρ = 0.58, whereas a similar/lower correlation was observed between the trans-diseases (JPN-SCZ vs JPN-BD/EAS-MDD, rg = 0.56/0.29) or trans-diseases/populations (JPN-SCZ vs PGC-BD/MDD, ρ = 0.38/0.12). In conclusion, (a) Fifteen novel loci are possible susceptibility genes for SCZ and (b) SCZ "risk" effect is shared with other psychiatric disorders even across populations.

Carbonyl Stress and Microinflammation-Related Molecules as Potential Biomarkers in Schizophrenia.

This literature review primarily aims to summarize our research, comprising both cross-sectional and longitudinal studies, and discuss the possibility of using microinflammation-related biomarkers as peripheral biomarkers in the diagnosis and monitoring of patients with schizophrenia. To date, several studies have been conducted on peripheral biomarkers to recognize the potential markers for the diagnosis of schizophrenia and to determine the state and effects of therapy in patients with schizophrenia. Research has established a correlation between carbonyl stress, an environmental factor, and the pathophysiology of neuropsychiatric diseases, including schizophrenia. In addition, studies on biomarkers related to these stresses have achieved results that are either replicable or exhibit consistent increases or decreases in patients with schizophrenia. For instance, pentosidine, an advanced glycation end product (AGE), is considerably elevated in patients with schizophrenia; however, low levels of vitamin B6 [a detoxifier of reactive carbonyl compounds (RCOs)] have also been reported in some patients with schizophrenia. Another study on peripheral markers of carbonyl stress in patients with schizophrenia revealed a correlation of higher levels of glyceraldehyde-derived AGEs with higher neurotoxicity and lower levels of soluble receptors capable of diminishing the effects of AGEs. Furthermore, studies on evoked microinflammation-related biomarkers (e.g., soluble tumor necrosis factor receptor 1) have reported relatively consistent results, suggesting the involvement of microinflammation in the pathophysiology of schizophrenia. We believe that our cross-sectional and longitudinal studies as well as various previous inflammation marker studies that could be interpreted from several perspectives, such as mild localized encephalitis and microvascular disturbance, highlighted the importance of early intervention as prevention and distinguished the possible exclusion of inflammations in schizophrenia.

High doses of antipsychotic polypharmacy are related to an increase in serum levels of pentosidine in patients with schizophrenia.

BACKGROUND: Carbonyl stress in patients with schizophrenia has been reported to be reflected by an increase in peripheral pentosidine levels. This cohort study tested whether the accumulation of pentosidine was related to the disease severity or the treatment (routine administration of high antipsychotic doses). METHODS: We followed up our original investigation using a new group of 137 patients with acute schizophrenia and 45 healthy subjects, and then pooled the two cohorts to conduct the following analysis on a total of 274 patients. The associations of serum pentosidine and pyridoxal levels with duration of education, estimated duration of medication, the severity of symptoms, and daily doses of antipsychotics, antiparkinsonian drugs, and anxiolytics were evaluated by multiple linear regression analysis. RESULTS: The combined cohort of 274 patients exhibited abnormally high serum levels of pentosidine, were associated with a higher daily dose of antipsychotic drugs and a longer estimated duration of medication without statistical significance of diagnosis. This was also observed in the patients treated with antipsychotic polypharmacy, but the serum pentosidine levels of patients treated with first- or second-generation antipsychotic monotherapy showed no relationship with these two variables. CONCLUSION: High levels of serum pentosidine were associated with high daily doses of antipsychotic drugs and a longer estimated duration of medication in patients treated with antipsychotic polypharmacy.

High serum soluble tumor necrosis factor receptor 1 predicts poor treatment response in acute-stage schizophrenia.

Inflammation may be involved in the pathophysiology of schizophrenia. However, few cross-sectional or longitudinal studies have examined changes in biomarker expression to evaluate diagnostic and prognostic efficacy in acute-stage schizophrenia. We compared serum inflammatory biomarker concentrations in 87 patients with acute-stage schizophrenia on admission to 105 age-, sex-, and body mass index (BMI)-matched healthy controls. The measured biomarkers were soluble tumor necrosis factor receptor 1 (sTNFR1) and adiponectin, which are associated with inflammatory responses, and pigment epithelium-derived factor (PEDF), which has anti-inflammatory properties. We then investigated biomarker concentrations and associations with clinical factors in 213 patients (including 42 medication-free patients) and 110 unmatched healthy controls to model conditions typical of clinical practice. Clinical symptoms were assessed using the Brief Psychiatric Rating Scale and Global Assessment of Function. In 121 patients, biomarker levels and clinical status were evaluated at both admission and discharge. Serum sTNFR1 was significantly higher in patients with acute-stage schizophrenia compared to matched controls while no significant group differences were observed for the other markers. Serum sTNFR1 was also significantly higher in the 213 patients compared to unmatched controls. The 42 unmedicated patients had significantly lower PEDF levels compared to controls. Between admission and discharge, sTNFR1 levels decreased significantly; however, biomarker changes did not correlate with clinical symptoms. The discriminant accuracy of sTNFR1 was 93.2% between controls and patients, showing no symptom improvement during care. Inflammation and a low-level anti-inflammatory state may be involved in both schizophrenia pathogenesis and acute-stage onset. High serum sTNFR1 in the acute stage could be a useful prognostic biomarker for treatment response in clinical practice.

Genetic association between RAGE polymorphisms and Alzheimer's disease and Lewy body dementias in a Japanese cohort: a case-control study.

BACKGROUND/AIMS: Interaction of receptor for advanced glycation end products (RAGE) with amyloid-ß increases amplification of oxidative stress and plays pathological roles in Alzheimer's disease (AD). Oxidative stress leads to α-synuclein aggregation and is also a major contributing factor in the pathogenesis of Lewy body dementias (LBDs). Therefore, we aimed to investigate whether RAGE gene polymorphisms were associated with AD and LBDs. METHODS: Four single nucleotide polymorphisms (SNPs)-rs1800624, rs1800625, rs184003, and rs2070600-of the gene were analyzed using a case-control study design comprising 288 AD patients, 76 LBDs patients, and 105 age-matched controls. RESULTS: Linkage disequilibrium (LD) examination showed strong LD from rs1800624 to rs2070600 on the gene (1.1 kb) in our cases in Japan. Rs184003 was associated with an increased risk of AD. Although there were no statistical associations for the other three SNPs, haplotypic analyses detected genetic associations between AD and the RAGE gene. Although relatively few cases were studied, results from the SNPs showed that they did not modify the risk of developing LBDs in the Japanese population. CONCLUSION: Our findings suggested that polymorphisms in the RAGE gene are involved in genetic susceptibility to AD. Copyright © 2016 John Wiley & Sons, Ltd.

Estimated cognitive decline in patients with schizophrenia: A multicenter study.

AIM: Studies have reported that cognitive decline occurs after the onset of schizophrenia despite heterogeneity in cognitive function among patients. The aim of this study was to investigate the degree of estimated cognitive decline in patients with schizophrenia by comparing estimated premorbid intellectual functioning and current intellectual functioning. METHODS: A total of 446 patients with schizophrenia (228 male, 218 female), consisting of three sample sets obtained from 11 psychiatric facilities, and 686 healthy controls participated in this study. The Wechsler Adult Intelligence Scale-III (WAIS-III) was used to measure the participants' current full-scale IQ (FSIQ). The premorbid IQ was estimated using the Japanese Adult Reading Test-25. Estimated cognitive decline (difference score) was defined as the difference between the estimated premorbid IQ and the current FSIQ. RESULTS: Patients with schizophrenia showed greater estimated cognitive decline, a lower FSIQ, and a lower premorbid IQ compared with the healthy controls. The mean difference score, FSIQ, and estimated premorbid IQ were -16.3, 84.2, and 100.5, respectively, in patients with schizophrenia. Furthermore, 39.7% of the patients had a difference score of 20 points or greater decline. A discriminant analysis showed that the difference score accurately predicted 81.6% of the patients and healthy controls. CONCLUSION: These results show the distribution of difference score in patients with schizophrenia. These findings may contribute to assessing the severity of estimated cognitive decline and identifying patients with schizophrenia who suffer from cognitive decline.

Usefulness of DNA Methylation Levels in COASY and SPINT1 Gene Promoter Regions as Biomarkers in Diagnosis of Alzheimer's Disease and Amnestic Mild Cognitive Impairment.

In order to conduct early therapeutic interventions for Alzheimer's disease (AD), convenient, early diagnosis markers are required. We previously reported that changes in DNA methylation levels were associated with amnestic mild cognitive impairment (aMCI) and AD. As the results suggested changes in DNA methylation levels in the COASY and SPINT1 gene promoter regions, in the present study we examined DNA methylation in these regions in normal controls (NCs, n = 30), aMCI subjects (n = 28) and AD subjects (n = 30) using methylation-sensitive high resolution melting (MS-HRM) analysis. The results indicated that DNA methylation in the two regions was significantly increased in AD and aMCI as compared to NCs (P < 0.0001, P < 0.0001, ANOVA). Further analysis suggested that DNA methylation in the COASY gene promoter region in particular could be a high sensitivity, high specificity diagnosis biomarker (COASY: sensitivity 96.6%, specificity 96.7%; SPINT1: sensitivity 63.8%, specificity 83.3%). DNA methylation in the COASY promoter region was associated with CDR Scale Sum of Boxes (CDR-SB), an indicator of dementia severity. In the SPINT1 promoter region, DNA methylation was negatively associated with age in NCs and elevated in aMCI and AD subjects positive for antibodies to Herpes simplex virus type 1 (HSV-1). These findings suggested that changes in DNA methylation in the COASY and SPINT1 promoter regions are influenced by various factors. In conclusion, DNA methylation levels in the COASY and SPINT1 promoter regions were considered to potentially be a convenient and useful biomarker for diagnosis of AD and aMCI.

Genetic Association between Presenilin 2 Polymorphisms and Alzheimer's Disease and Dementia of Lewy Body Type in a Japanese Population.

BACKGROUND/AIMS: Mutations in the presenilin 2 (PSEN2) gene cause familial Alzheimer's disease (AD). Common polymorphisms affect gene activity and increase the risk of AD. Nonsynonymous polymorphisms in the PSEN2 gene showed Lewy body dementia (LBD) phenotypes clinically. Therefore, we aimed to investigate whether PSEN2 gene polymorphisms were associated with AD or LBD. METHODS: Seven single nucleotide polymorphisms (SNPs) of the gene were analyzed using a case-control study design comprising 288 AD patients, 76 LBD patients, and 105 age-matched controls. RESULTS: Linkage disequilibrium (LD) examination showed strong LD from rs1295645 to rs8383 on the gene in our cases from Japan. There were no associations between the SNPs studied here and AD onset, and haplotypic analyses did not detect genetic associations between AD and the PSEN2 gene. Although the number of the cases was small, the SNPs studied did not modify the risk of developing LBD in a Japanese population. CONCLUSION: The common SNPs of the PSEN2 gene did not affect the risk of AD or LBD in a Japanese population. Because genetic variability of the PSEN2 gene is associated with behavioral and psychological symptoms of dementia (BPSD) in AD and LBD, further detailed analyses considering BPSD of both diseases would be required.

Association of copy number polymorphisms at the promoter and translated region of COMT with Japanese patients with schizophrenia.

Chromosome 22q11.2 deletion syndrome and genetic variations including single-nucleotide polymorphism (SNP) and copy number variation (CNV) in catechol-O-methyltransferase (COMT) situated at 22q11.2 remains controversial. Here, the genetic relationship between COMT and Japanese patients with schizophrenia was investigated by examining whether the SNPs correlated with schizophrenia based on a common disease-common variant hypothesis. Additionally, 22q11.2DS were screened based on a common disease-rare variant hypothesis; low-frequency CNVs situated at two COMT promoters and exons were investigated based on the low-frequency variants with an intermediate effect; and positive findings from the first stage were reconfirmed using a second-stage replication study including a larger sample size. Eight SNPs and 10 CNVs were investigated using Taqman SNP and CNV quantitative real-time polymerase chain reaction method. For the first-stage analysis, 513 unrelated Japanese patients with schizophrenia and 705 healthy controls were examined. For the second-stage replication study, positive findings from the first stage were further investigated using a larger sample size, namely 1,854 patients with schizophrenia and 2,137 controls. The first-stage analysis showed significant associations among schizophrenia, intronic SNP rs165774, CNV6 situated at promoter 1, CNV8 at exon 6, and CNV9 at exon 7. The second-stage study showed that intronic SNP rs165774 (χ(2) = 8.327, P = 0.0039), CNV6 (χ(2) = 19.66, P = 0.00005), and CNV8 (χ(2) = 16.57, P = 0.00025) were significantly associated with schizophrenia. Large and rare CNVs as well as low-frequency CNVs and relatively small CNVs, namely <30 kb in COMT, may be genetic risk factors for schizophrenia.

Emerging roles of ARHGAP33 in intracellular trafficking of TrkB and pathophysiology of neuropsychiatric disorders.

Intracellular trafficking of receptor proteins is essential for neurons to detect various extracellular factors during the formation and refinement of neural circuits. However, the precise mechanisms underlying the trafficking of neurotrophin receptors to synapses remain elusive. Here, we demonstrate that a brain-enriched sorting nexin, ARHGAP33, is a new type of regulator for the intracellular trafficking of TrkB, a high-affinity receptor for brain-derived neurotrophic factor. ARHGAP33 knockout (KO) mice exhibit reduced expression of synaptic TrkB, impaired spine development and neuropsychiatric disorder-related behavioural abnormalities. These deficits are rescued by specific pharmacological enhancement of TrkB signalling in ARHGAP33 KO mice. Mechanistically, ARHGAP33 interacts with SORT1 to cooperatively regulate TrkB trafficking. Human ARHGAP33 is associated with brain phenotypes and reduced SORT1 expression is found in patients with schizophrenia. We propose that ARHGAP33/SORT1-mediated TrkB trafficking is essential for synapse development and that the dysfunction of this mechanism may be a new molecular pathology of neuropsychiatric disorders.

Benefits of use, and tolerance of, medium-chain triglyceride medical food in the management of Japanese patients with Alzheimer's disease: a prospective, open-label pilot study.

OBJECTIVES: This is the first clinical trial of this type in Japan, designed to analyze two important aspects of Alzheimer's disease (AD) management using medium-chain triglycerides. Axona was administered for 3 months (40 g of powder containing 20 g of caprylic triglycerides). We used an indurating, four-step dose-titration method (from 10 to 40 g per day) for 7 days before the trial, and examined the tolerance and adverse effects of this intervention. We also investigated its effect on cognitive function in mild-to-moderate AD patients. PATIENTS AND METHODS: This was a clinical intervention in 22 Japanese patients with sporadic AD at a mild-to-moderate stage (ten females, 12 males), mean age (± standard deviation) 63.9 (±8.5) years, Mini-Mental State Examination (MMSE) score, 10-25, seven patients were ApoE4-positive. During Axona administration, we examined changes in cognitive function by obtaining MMSE and AD assessment-scale scores. Intolerance and serum ketone concentrations were also examined. RESULTS: The tolerance of Axona was good, without severe gastrointestinal adverse effects. Axona did not improve cognitive function in our sample of AD patients, even in those patients without the ApoE4 allele. However, some ApoE4-negative patients with baseline MMSE score ≥14 showed improvement in their cognitive functions. CONCLUSION: The modified dose-titration method, starting with a low dose of Axona, decreased gastrointestinal adverse effects in Japanese patients. Axona might be effective for some relatively mildly affected patients with AD (with cognitive function MMSE score of ≥14 and lacking the ApoE4 allele).

Development of Biomarkers Based on DNA Methylation in the NCAPH2/LMF2 Promoter Region for Diagnosis of Alzheimer's Disease and Amnesic Mild Cognitive Impairment.

From the standpoint of early interventions for dementia, a convenient method of diagnosis using biomarkers is required for Alzheimer's disease (AD) in the early stage as well as amnesic mild cognitive impairment (aMCI). Focusing on differences in DNA methylation due to AD and aMCI, in the present study, we first conducted genome-wide screening, measuring blood DNA methylation levels by the Illumina Infinium HD Methylation Assay in 3 small age-and gender-matched groups consisting of 4 subjects each: normal controls (NC), aMCI and AD. The genome-wide analysis produced 11 DNA methylation loci that distinguished the 3 groups. For confirmation, we increased group sizes and examined samples by pyrosequencing which revealed that DNA methylation in the NCAPH2/LMF2 promoter region was significantly decreased in the AD (n = 30) and aMCI (n = 28) groups as compared to the NC group (n = 30) (P < 0.0001, ANCOVA). No association was found between methylation levels and APOE genotype. NCAPH2/LMF2 methylation levels were considered to potentially be a convenient and useful biomarker for diagnosis of AD and aMCI.

Genetic or Psychogenic? A Case Study of "Folie à Quatre" Including Twins.

Shared psychotic disorder, characterized by shared delusion among two or more subjects (termed "Folie à deux," "trois," etc.), is often associated with strong religious beliefs or social isolation, factors creating strong psychological sympathy. Recently, we treated a rare familial case of "Folie à quatre" in central Tokyo without such influences. The proband was a schizophrenia patient and younger brother within monozygotic twins. Positive symptoms were "transmitted" to remaining family members, his elder brother, mother, and father father, in a relatively short period of three months. Although the pathophysiology of these positive symptoms (delusions and hallucinations) remains unclear, the transmission pattern suggests the primacy of social and environmental factors (and/or their interaction), while genetics appeared less influential in this "Folie à famille." Although undiagnosed psychoses in the whole family cannot be excluded, they did not share the other negative schizophrenia symptoms of the proband. A strong familial connection appeared to be the most important factor for the common delusion and hallucination.

Associations of common copy number variants in glutathione S-transferase mu 1 and D-dopachrome tautomerase-like protein genes with risk of schizophrenia in a Japanese population.

Oxidative-stress, genetic regions of interest (1p13 and 22q11), and common copy number variations (CNVs) may play roles in the pathophysiology of schizophrenia. In the present study, we confirmed associations between schizophrenia and the common CNVs in the glutathione (GSH)-related genes GSTT1, DDTL, and GSTM1 using quantitative real-time polymerase chain reaction analyses of 620 patients with schizophrenia and in 622 controls. No significant differences in GSTT1 copy number distributions were found between patient groups. However, frequencies of characterized CNVs and assumed gain alleles of DDTL and GSTM1 were significantly higher in patients with schizophrenia. In agreement with a previous report, the present data indicate that gains in the CNV alleles DDTL and GSTM1 are genetic risk factors in Japanese patients with schizophrenia, and suggest involvement of micro-inflammation and oxidative stress in the pathophysiology of schizophrenia.