Serum high-sensitivity C-reactive protein and dementia in a community-dwelling Japanese older population (JPSC-AD).

In recent years, the association between neuroinflammatory markers and dementia, especially Alzheimer's disease (AD), has attracted much attention. However, the evidence for the relationship between serum-hs-CRP and dementia including AD are inconsistent. Therefore, the relationships of serum high-sensitivity CRP (hs-CRP) with dementia including AD and with regions of interest of brain MRI were investigated. A total of 11,957 community residents aged 65 years or older were recruited in eight sites in Japan (JPSC-AD Study). After applying exclusion criteria, 10,085 participants who underwent blood tests and health-related examinations were analyzed. Then, serum hs-CRP levels were classified according to clinical cutoff values, and odds ratios for the presence of all-cause dementia and its subtypes were calculated for each serum hs-CRP level. In addition, the association between serum hs-CRP and brain volume regions of interest was also examined using analysis of covariance with data from 8614 individuals in the same cohort who underwent brain MRI. After multivariable adjustment, the odds ratios (ORs) for all-cause dementia were 1.04 (95% confidence interval [CI] 0.76-1.43), 1.68 (95%CI 1.08-2.61), and 1.51 (95%CI 1.08-2.11) for 1.0-1.9 mg/L, 2.0-2.9 mg/L, and ≥ 3.0 mg/L, respectively, compared to < 1.0 mg/L, and those for AD were 0.72 (95%CI 0.48-1.08), 1.76 (95%CI 1.08-2.89), and 1.61 (95%CI 1.11-2.35), for 1.0-1.9 mg/L, 2.0-2.9 mg/L, and ≥ 3.0 mg/L, respectively, compared to < 1.0 mg/L. Multivariable-adjusted ORs for all-cause dementia and for AD prevalence increased significantly with increasing serum hs-CRP levels (p for trend < 0.001 and p = 0.001, respectively). In addition, the multivariable-adjusted temporal cortex volume/estimated total intracranial volume ratio decreased significantly with increasing serum hs-CRP levels (< 1.0 mg/L 4.28%, 1.0-1.9 mg/L 4.27%, 2.0-2.9 mg/L 4.29%, ≥ 3.0 mg/L 4.21%; p for trend = 0.004). This study's results suggest that elevated serum hs-CRP levels are associated with greater risk of presence of dementia, especially AD, and of temporal cortex atrophy in a community-dwelling Japanese older population.

Functional AGXT2 SNP rs180749 variant and depressive symptoms: Baseline data from the Aidai Cohort Study in Japan.

No study has shown the relationship between alanine-glyoxylate aminotransferase 2 (AGXT2) single nucleotide polymorphisms (SNPs) and depressive symptoms. The present case-control study examined this relationship in Japanese adults. Cases and control participants were selected from those who participated in the baseline survey of the Aidai Cohort Study, which is an ongoing cohort study. Cases comprised 280 participants with depressive symptoms based on a Center for Epidemiologic Studies Depression Scale (CES-D) score ≥ 16. Control participants comprised 2034 participants without depressive symptoms based on the CES-D who had not been diagnosed by a physician as having depression or who had not been currently taking medication for depression. Adjustment was made for age, sex, smoking status, alcohol consumption, leisure time physical activity, education, body mass index, hypertension, dyslipidemia, and diabetes mellitus. Compared with the GG genotype of rs180749, both the GA and AA genotypes were significantly positively associated with the risk of depressive symptoms assessed by the CES-D: the adjusted odds ratios for the GA and AA genotypes were 2.83 (95% confidence interval [CI] 1.23-8.24) and 3.10 (95% CI 1.37-8.92), respectively. The TGC haplotype of rs37370, rs180749, and rs16899974 was significantly inversely related to depressive symptoms (crude OR 0.67; 95% CI 0.49-0.90), whereas the TAC haplotype was significantly positively associated with depressive symptoms (crude OR 1.24; 95% CI 1.01-1.52). This is the first study to show significant associations between AGXT2 SNP rs180749, the TGC haplotype, and the TAC haplotype and depressive symptoms.

Practical clinical guidelines and pharmacological treatment for attention-deficit hyperactivity disorder in Asia.

Attention-deficit hyperactivity disorder (ADHD) is characterized by persistent symptoms of inattention, hyperactivity, and impulsivity. Both, stimulant and nonstimulant medications have been approved for the treatment of this disorder. Several Western guidelines recommend the use of prescribed Food and Drug Administration (FDA)-approved medications for ADHD along with parental training in behavior management and behavioral classroom intervention. In 2022, new Japanese guidelines for ADHD were issued, which recommended school environment management and psychosocial treatment as the first-line treatment, with pharmacological treatment added as the second-line treatment. Although Japanese guidelines, including pharmacological treatments, have been established, the guidelines and utilization of ADHD medications across Asian regions are unclear. Therefore, to appropriately evaluate the strategy of pharmacological treatments for ADHD, we investigated Asian regional guidelines for ADHD medication in children. We also reviewed the guidelines in Malaysia, Singapore, India, and the Republic of Korea and found that these guidelines differ from Western guidelines.

Effects of gestational haloperidol exposure on mRNA expressions related to glutamate and GABA receptors in offspring.

Antipsychotic treatment is vital for patients with schizophrenia even in the perinatal period, but the impact at the molecular biological level on offspring is unclear. The aim of the present study was to investigate the effects of intraperitoneal haloperidol injection to pregnant mice on glutamate and GABA receptors in the brain of offspring mice. Eight-week-old pregnant mice were treated with either intraperitoneal haloperidol or normal saline injection, and their offspring were defined as F1 mice. In addition, eight-week-old male mice were used as acute mice that were intraperitoneally injected with haloperidol or normal saline for 20 days. mRNA expression levels were measured by RT-qPCR. Western blotting was performed of the frontal lobes of F1 mice. In the hippocampi of F1 mice, Grik3 (p = 0.023) and Gabra3 (p = 0.004) mRNA expression levels were significantly higher in the haloperidol group than in the control group, whereas Gria2 (p < 0.001) and Grin2a (p < 0.001) mRNA expression levels were significantly lower in the haloperidol group than in the control group. Gria2 (p = 0.015), and Grik3 (p = 0.037), and Grin2a (p = 0.012) mRNA expression levels were significantly lower in the haloperidol group than in the control group in the frontal lobes of F1 mice. In the hippocampi of acute mice, Grik3 (p = 0.049) and Gabra3 (p = 0.007) mRNA expression levels were significantly decreased in the haloperidol group. Fetal exposure to haloperidol can affect glutamate and GABA receptors through mRNA expression changes in the brain of offspring.

Factors associated with quality of life in patients receiving palliative radiotherapy for bone metastases: a secondary cross-sectional analysis of data from a prospective multicenter observational study.

OBJECTIVE: To identify factors significantly associated with quality of life (QOL) and determine if these associations are strong enough to predict certain aspects of QOL without measuring them. METHODS: We conducted an exploratory secondary analysis of baseline data of 224 patients (enrolled between December 2020 and March 2021) from a previously published prospective observational study on radiotherapy for bone metastases at 26 centres. Using univariable linear regression, we assessed the association between patient/treatment factors and QOL scale scores as measured by the European Organization for Research and Treatment of Cancer (EORTC) QOL Questionnaire Core 15-Palliative (QLQ-C15-PAL) and the EORTC QOL Questionnaire Bone Metastases module (QLQ-BM22). RESULTS: Age and sex were not significantly associated with QOL. Worse performance status, higher pain scores, and opioid and single-fraction use were significantly associated with most QOL scales; these four factors were associated with worse global QOL, worse functioning status, and more severe symptoms. The coefficients of determination for most QOL scales were less than 0.2, indicating that most of the variability in QOL scores was not explained by any of the explanatory variables. CONCLUSION: Performance status, pain intensity, and opioid and single-fraction use were significantly associated with most QOL scales. However, the associations were not strong enough to estimate QOL. ADVANCES IN KNOWLEDGE: To date, the association between treatment factors and QOL in patients with bone metastases has not been fully studied. We identified the factors that were significantly associated with QOL and found that these associations were not strong enough to predict QOL.

Analysis of factors related to cognitive impairment in a community-based, complete enumeration survey in Japan: the Nakayama study.

BACKGROUND: The number of patients with cognitive disorders is rapidly increasing in the world, becoming not only a medical problem, but also a social problem. There have been many reports that various factors are associated with cognitive dysfunction, but the factors have not yet been fully identified. This was a community-based complete enumeration study which aimed to identify risk and protective factors for dementia. METHODS: The first phase included all residents aged 65 years or older in a town in Japan. They completed many examinations, such as living conditions questionnaires, physical examination, Mini-Mental State Examination, and brain magnetic resonance imaging. The participants with suspected cognitive impairment underwent additional examinations for detailed evaluation in the second phase. Statistical analysis was performed to identify risk and protective factors for dementia after all participants were diagnosed. RESULTS: There were 927 participants in the baseline evaluation; 611 (65.9%) were healthy, 165 (17.8%) had mild cognitive impairment (MCI), and 151 (16.3%) had dementia. The age-standardised prevalence of dementia was 9.5%. Statistical analyses for amnestic MCI and Alzheimer's disease showed that risk factors for cognitive decline were diabetes mellitus, low activities of daily living, and living alone, and that protective factors were history of exercise and drinking habit. CONCLUSION: The present findings suggest that several lifestyle-related diseases and factors are associated with cognitive decline. These results support similar findings from previous studies and will be helpful for preventing dementia in the future.

School teachers' awareness of internet addiction in elementary school students: a regional survey in Japan.

In recent years, concerns about internet addiction (IA) among children have been increasing. This study focused on the awareness of IA in elementary school teachers. A web-based anonymous survey was conducted in November 2021. The participants completed an original questionnaire about their awareness of IA. The participants were divided into three groups based on their positions in the classroom: class teachers, support teachers, and administrative teachers. Out of 283 participants, over 70% had not approached students with IA and had little practical knowledge about the disorder. Support and administrative teachers had more opportunities to interact with students with IA than class teachers (p < 0.001 in both cases). Support teachers had more opportunities to ask their colleagues about IA than class teachers (p < 0.01); similarly, administrative teachers also had more opportunities to discuss IA with colleagues than class teachers (p = 0.04). Preventive interventions are recommended for people who communicate with children with IA. Students with IA might cause anxiety among teachers; therefore, preventive education strategies should be implemented with the cooperation of psychiatrists, psychologists, and public health nurses.

Aberrant Expression of GABA-Related Genes in the Hippocampus of 3xTg-AD Model Mice from the Early to End Stages of Alzheimer's Disease.

BACKGROUND: We explored the gene expression levels in the brain of 3xTg-AD model mice to elucidate the molecular pathological changes from the early to end stages of Alzheimer's disease (AD). OBJECTIVE: We re-analyzed our previously published microarray data obtained from the hippocampus of 3xTg-AD model mice at 12 and 52 weeks of age. METHODS: Functional annotation and network analyses of the up- and downregulated differentially expressed genes (DEGs) in mice aged 12 to 52 weeks were performed. Validation tests for gamma-aminobutyric acid (GABA)-related genes were also performed by quantitative polymerase chain reaction (qPCR). RESULTS: In total, 644 DEGs were upregulated and 624 DEGs were downregulated in the hippocampus of both the 12- and 52-week-old 3xTg-AD mice. In the functional analysis of the upregulated DEGs, 330 gene ontology biological process terms, including immune response, were found, and they interacted with each other in the network analysis. In the functional analysis of the downregulated DEGs, 90 biological process terms, including several terms related to membrane potential and synapse function, were found, and they also interacted with each other in the network analysis. In the qPCR validation test, significant downregulation was seen for Gabrg3 at the ages of 12 (p = 0.02) and 36 (p = 0.005) weeks, Gabbr1 at the age of 52 weeks (p = 0.001), and Gabrr2 at the age of 36 weeks (p = 0.02). CONCLUSION: Changes in immune response and GABAergic neurotransmission may occur in the brain of 3xTg mice from the early to end stages of AD.

Online training of Covid-19 infection prevention and control for healthcare workers in psychiatric institutes.

BACKGROUND: This study aimed to develop a unique online infection prevention and control (IPC) training on Covid-19 for healthcare workers in psychiatric institutes in Japan and to examine its efficacy based on its impact on the knowledge, attitude, and confidence about IPC for Covid-19 among the healthcare workers. METHOD: This quasi-experimental study was conducted using online training on Covid-19 IPC for healthcare workers in various psychiatric institutes from April 2021 to March 2022. An online training video on Covid-19 IPC was developed. Voluntary healthcare workers in psychiatric institutes located in five prefectures in Japan were recruited to participate in this training. The participants then completed 30 min of online training and surveys about knowledge, attitude, and confidence were conducted pre, post, and three months after the training. The video training and surveys were contextually validated by the experts, but not by any previous study. RESULTS: A total of 224 participants were included, of which 108 (54.0%) were men. The mean (standard deviation (SD)) age and the mean occupational experience were 47.4 (9.5) and 18.0 (12.6) years, respectively. Among the participants, 190 (84.8%) completed the post-training, and 131 (58.5%) completed the three-month-later training surveys. The total score on the quizzes in the post-training (+ 31.1%, SD 15.7, p-value < 0.01) and three-month-later training (+ 14.9%, SD 16.8, p-value < 0.01) surveys had significantly increased from that in the pre-training survey. In contrast, the total score in the three-month-later training had significantly decreased from that in the post-training survey (-16.1%, SD 16.7, p-value < 0.01). CONCLUSION: Thirty minutes of online training about IPC for Covid-19 had improved knowledge, confidence, and attitude among psychiatric healthcare workers. Regular online training would help in preventing the transmission or formation of clusters of Covid-19 in psychiatric healthcare institutes.

Gestational exposure to haloperidol changes Cdkn1a and Apaf1 mRNA expressions in mouse hippocampus.

BACKGROUND: The onset of schizophrenia is associated with both genetic and environmental risks during brain development. Environmental factors during pregnancy can represent risk factors for schizophrenia, and we have previously reported that several microRNA and mRNA expression changes in fetal brains exposed to haloperidol during pregnancy may be related to the onset of this disease. This study aimed to replicate that research and focused on apoptotic-related gene expression changes. METHODS: Haloperidol (1 mg/kg) or aripiprazole (1 mg/kg) was injected into pregnant mice. Using RNA sequencing for the hippocampus of each offspring born from pregnant mice exposed to haloperidol, we analyzed genes identified as changed in our previous report and validated two apoptosis-related genes (Cdkn1a and Apaf1) using quantitative polymerase chain reaction (qPCR) methods. Furthermore, we attempted to elucidate the direct effects of haloperidol and aripiprazole on those mRNA expressions in in vitro experiments. RESULTS: RNA sequencing successfully replicated 16 up-regulated and 5 down-regulated genes in this study. Of those, up-regulations of Cdkn1a and Apaf1 mRNA expression were successfully validated by direct quantification. Moreover, haloperidol and aripiprazole dose-dependent upregulation of both mRNA expressions were confirmed in a Neuro2a cell line. CONCLUSIONS: In the hippocampus of offspring, intraperitoneal injection of haloperidol to pregnant mice induced up-regulation of apoptotic genes that representing the phenotypic change without apoptosis. These findings will be useful for understanding the molecular biological mechanisms underlying the effects of antipsychotics on the fetal brain.

Dramatically Improved Severe Pulmonary Arterial Hypertension Caused by Qing-Dai (Chinese Herbal Drug) for Ulcerative Colitis.

Pulmonary arterial hypertension (PAH) is a rare and fatal disease for which some causative drugs have been developed. Qing-Dai is a Chinese herbal drug that is sometimes used as a specific treatment for ulcerative colitis in Asia, including Japan. Here, we report a case of severe Qing-Dai-induced PAH. A 19-year-old woman who has been taking Qing-Dai for 8 months was admitted for exertional dyspnea. Her mean pulmonary artery pressure dramatically improved from 72 to 18 mmHg with Qing-Dai discontinuation and PAH-specific therapy. After 6 years of onset, she had not relapsed with PAH with PAH-specific therapy.

Interferon signaling and hypercytokinemia-related gene expression in the blood of antidepressant non-responders.

Only 50% of patients with depression respond to the first antidepressant drug administered. Thus, biomarkers for prediction of antidepressant responses are needed, as predicting which patients will not respond to antidepressants can optimize selection of alternative therapies. We aimed to identify biomarkers that could predict antidepressant responsiveness using a novel data-driven approach based on statistical pattern recognition. We retrospectively divided patients with major depressive disorder into antidepressant responder and non-responder groups. Comprehensive gene expression analysis was performed using peripheral blood without narrowing the genes. We designed a classifier according to our own discrete Bayes decision rule that can handle categorical data. Nineteen genes showed differential expression in the antidepressant non-responder group (n = 15) compared to the antidepressant responder group (n = 15). In the training sample of 30 individuals, eight candidate genes had significantly altered expression according to quantitative real-time polymerase chain reaction. The expression of these genes was examined in an independent test sample of antidepressant responders (n = 22) and non-responders (n = 12). Using the discrete Bayes classifier with the HERC5, IFI6, and IFI44 genes identified in the training set yielded 85% discrimination accuracy for antidepressant responsiveness in the 34 test samples. Pathway analysis of the RNA sequencing data for antidepressant responsiveness identified that hypercytokinemia- and interferon-related genes were increased in non-responders. Disease and biofunction analysis identified changes in genes related to inflammatory and infectious diseases, including coronavirus disease. These results strongly suggest an association between antidepressant responsiveness and inflammation, which may be useful for future treatment strategies for depression.

A Retrospective Study of Patients Undergoing Palliative Radiotherapy for Airway Obstruction due to Lung Cancer.

BACKGROUND/AIM: In advanced stage lung cancer, bulky tumors can cause serious symptoms such as malignant airway obstruction (MAO). Prompt response to airway obstruction might be essential to improve quality of life and prolong life expectancy. Palliative external beam radiotherapy (EBRT) is a less invasive and highly safe treatment method that can alleviate symptoms and at the same time treat lung cancer. However, there are few reports on the results of palliative radiotherapy performed for improving airway obstruction and obstructive pneumonia. Therefore, this study retrospectively examined the effectiveness of palliative radiotherapy. PATIENTS AND METHODS: We reviewed 38 lung cancer patients with MAO who underwent EBRT. Patients were treated with a median dose of 37.5 Gy (range=30-40 Gy) in 10-20 fractions. Whether a patient was a responder or non-responder was assessed by whether the bronchus that was obstructed before EBRT reopened or improvement of obstructive pneumonia was observed on follow-up chest X-ray or computed tomography after EBRT. RESULTS: The median survival time was 135 days (range=31-469 days) for the responders to EBRT and 45 days (range=23-355 days) for non-responders; this difference was statistically significant (p=0.03). One-year overall survival rate was 18.5% and 0% for the responders to EBRT and non-responders, respectively. CONCLUSION: Palliative EBRT might be an important option for non-curative lung cancer patients with MAO.

Effects of social media on body dissatisfaction in junior high school girls in Japan.

AIMS: Body dissatisfaction (BD) is a serious problem related to the incidence of eating disorders. Social media (SM) use is known to be associated with BD. With a view to preventing the incidence of eating disorders, this study aimed to investigate the association between SM and BD, particularly, the role of SM in the encouragement of thinness and its relationship with adolescent girls' BD. METHODS: Junior high school girls aged 12-15 in Japan completed the Body Shape Questionnaire (BSQ), Eating Attitudes Test-26, Bulimic Investigatory Test Edinburgh, Depression Self-Rating Scale for Children, and SM usage. Participants were classified into two groups based on their BSQ cut-off score. RESULTS: Overall, 161 students were recruited (44 participants with BD; 117 without BD). The BD group used SM more than the non-BD group (χ2 (1) = 4.61, p = .032). The frequency of following SM accounts related to thinness was significantly higher in the BD group than in the non-BD group (χ2 (1) = 7.76, p = .005). The association between BD and following SM accounts focused on thinness was the most important (adjusted OR = 3.82; 95 % CI: 1.05-13.89). CONCLUSIONS: The risks of SM use increasing BD in adolescent girls should be considered to prevent mental disorders, including eating disorders.

Radiotherapy for ductal carcinoma of the prostate: an analysis based on the Japanese radiation oncology study group survey.

BACKGROUND: The clinical characteristics of prostate ductal carcinoma is still unclear, and treatment strategy has not yet been established due to its rarity. Therefore, we conducted a multicenter survey of radiation therapy for prostate ductal carcinoma in Japan. METHOD: Data of patients with ductal carcinoma of the prostate treated with radiation therapy between 1996 and 2018 were extracted from the database of each facility. RESULTS: Fifty-two treatment records of 41 patients were collected from nine institutions. The treatment purpose and situations were varied curative intent to palliation. Twenty-eight patients received curative treatments. The median follow-up period of these patients was 68 months. Androgen deprivation therapy was combined with radiation therapy in 26 cases (93%). X-ray and particle irradiation was used. Radiation dose range was 63-78 Gy; 5-year overall survival, progression-free survival and biochemical relapse-free survival were 87.0, 79.3 and 79.3%, respectively. One patient experienced Grade 3 radiation proctitis and one experienced Grade 3 radiation cystitis. There were no Grade 4 or worse adverse events. CONCLUSION: Most patient received similar treatment with adenocarcinoma of prostate, and the clinical results were compatible. For more reliable evidence, further studies are required.

Impact of clozapine on the expression of miR-675-3p in plasma exosomes derived from patients with schizophrenia.

OBJECTIVES: Recently, the expression changes of microRNAs (miRNAs) in the serum exosomes (EXO) of schizophrenia (SCZ) have been reported. The aim of this study was to investigate the global expression changes of miRNA derived from the plasma EXO of patients with treatment-resistant schizophrenia (TRS) and the effects of clozapine on miRNA expression. METHODS: Global miRNA expression changes in plasma EXO between TRS and controls were studied using microarray analysis. Then, miRNA expressions among TRS, non-TRS, and controls were confirmed with quantitative qPCR experiments. We also studied changes in EXO miRNA expression with in-vitro SH-SY5Y cells. RESULTS: A microarray for miRNA expression analysis (nine controls vs. nine patients with TRS) revealed 13 up- and 18 downregulated miRNAs that were relevant to neuronal and brain development based on gene ontology analysis. Of those, upregulated miR-675-3p expression was successfully validated in the same cohort by qPCR experiments. Conversely, miR-675-3p expression levels were significantly decreased in the non-TRS cohort (50 controls vs. 50 patients without TRS without clozapine treatment). CONCLUSIONS: We identified global miRNA changes in plasma EXO derived from patients with SCZ that were relevant to neuronal functions, among which, hsa-miR-675-3p expression was upregulated by clozapine treatment.

Prevalence of Comorbid Dementia in Late-life Depression and Bipolar Disorder: A Retrospective Inpatient Study.

Background: Dementia in patients with late-life mood disorders is clinically important. Objective: We aimed to investigate the prevalence of dementia in patients with late-life major depressive disorder (MDD) or bipolar disorder (BD) and to clarify the clinical characteristics associated with the diagnosis of dementia. Methods: The prevalence of dementia at hospital discharge and the clinical characteristics at hospitalization who are diagnosed with MDD or BD over 65 years of age, from the medical records of 684 patients who had been admitted from 2015 to 2020 were investigated. Results: A total of 66 patients with MDD (n = 50) and BD (n = 16) were analyzed. The prevalence of dementia was significantly higher in MDD than in BD (24.0% versus 0%; p = 0.026). The mean age at onset of MDD was significantly older in the MDD with dementia group than in the MDD without (76.9±6.3 years versus 62.2±14.0 years; p < 0.001). The rate of first depressive episode at this admission was significantly higher in the MDD with dementia group (91.7% versus 30.3%; p < 0.001). The diagnosis of dementia was significantly associated with lower scores for "insomnia early" (p = 0.019) and higher scores for "insight" (p = 0.049) on the 17-item Hamilton Depression Rating (HAMD-17) subscales and lower scores for "recall" (p = 0.003) on the MMSE subscales. Conclusion: The older age of first onset of depression, "insomnia early", "insight" and "recall" may be useful indicators for a diagnosis of dementia in late-life depression.

Metabolomic alterations in the blood plasma of older adults with mild cognitive impairment and Alzheimer's disease (from the Nakayama Study).

Alzheimer's disease (AD) is a progressive disease, and the number of AD patients is increasing every year as the population ages. One of the pathophysiological mechanisms of AD is thought to be the effect of metabolomic abnormalities. There have been several studies of metabolomic abnormalities of AD, and new biomarkers are being investigated. Metabolomic studies have been attracting attention, and the aim of this study was to identify metabolomic biomarkers associated with AD and mild cognitive impairment (MCI). Of the 927 participants in the Nakayama Study conducted in Iyo City, Ehime Prefecture, 106 were selected for this study as Control (n = 40), MCI (n = 26), and AD (n = 40) groups, matched by age and sex. Metabolomic comparisons were made across the three groups. Then, correlations between metabolites and clinical symptoms were examined. The blood mRNA levels of the ornithine metabolic enzymes were also measured. Of the plasma metabolites, significant differences were found in ornithine, uracil, and lysine. Ornithine was significantly decreased in the AD group compared to the Control and MCI groups (Control vs. AD: 97.2 vs. 77.4; P = 0.01, MCI vs. AD: 92.5 vs. 77.4; P = 0.02). Uracil and lysine were also significantly decreased in the AD group compared to the Control group (uracil, Control vs. AD: 272 vs. 235; P = 0.04, lysine, Control vs. AD: 208 vs. 176; P = 0.03). In the total sample, the MMSE score was significantly correlated with lysine, ornithine, thymine, and uracil. The Barthel index score was significantly correlated with lysine. The instrumental activities of daily living (IADL) score were significantly correlated with lysine, betaine, creatine, and thymine. In the ornithine metabolism pathway, the spermine synthase mRNA level was significantly decreased in AD. Ornithine was decreased, and mRNA expressions related to its metabolism were changed in the AD group compared to the Control and MCI groups, suggesting an association between abnormal ornithine metabolism and AD. Increased betaine and decreased methionine may also have the potential to serve as markers of higher IADL in elderly persons. Plasma metabolites may be useful for predicting the progression of AD.

Functional AGXT2 SNP rs37369 Variant Is a Risk Factor for Diabetes Mellitus: Baseline Data From the Aidai Cohort Study in Japan.

OBJECTIVES: The relationship between alanine-glyoxylate aminotransferase 2 (AGXT2) single-nucleotide polymorphisms (SNPs) and diabetes mellitus (DM) has not been investigated. Therefore, we performed a case-control study to examine this relationship. METHODS: The study subjects included 2,390 Japanese men and women aged 34 to 88 years. In total, 190 cases were defined as having a fasting plasma glucose level ≥126 mg/dL, having a glycated hemoglobin ≥6.5% or currently using diabetic medication. The 2,200 remaining participants served as control subjects. RESULTS: Compared with study subjects with the CC genotype of AGXT2 SNP rs37369, those with the TT, but not CT, genotype had a significantly increased risk of DM: the adjusted odds ratio (OR) for the TT genotype was 1.83 (95% confidence interval [CI], 1.04 to 3.47). AGXT2 SNPs rs37370 and rs180749 were not significantly associated with the risk of DM. The CTA haplotype of rs37370, rs37369 and rs180749 was significantly positively associated with the risk of DM (crude OR, 1.25; 95% CI, 1.01 to 1.56), whereas the CCA haplotype was significantly inversely related to DM (crude OR, 0.53; 95% CI, 0.27 to 0.95). The multiplicative interaction between AGXT2 SNP rs37369 and smoking status with regard to the risk of DM was not significant (p=0.32 for interaction). CONCLUSIONS: This is the first study to show significant associations between AGXT2 SNP rs37369, the CTA haplotype, and the CCA haplotype and DM. No interaction with regard to the risk of DM was observed between rs37369 and smoking.