Yukiko Tomioka, Masahito Nakataki, Hidehiro Umehara, Tomohiro Yoshida, Hiroya Matsuda, Yui Matsumoto, Mariko Aoki, Yuri Yoshida, Yuichiroh Kamiyama, Tomohiko Nakayama, Naoki Yamada and Shusuke Numata : DNMT gene expression in peripheral leukocytes in schizophrenia and correlations with one-carbon metabolites: folate, total homocysteine, and vitamin B6., Frontiers in Psychiatry, 16, 2026.
(要約)
Previous studies have identified alterations in one-carbon metabolism (OCM), including DNA methylation abnormalities, in individuals with schizophrenia. However, the precise etiology of this disorder remains unclear. In the present study, we examined variations in the expression of DNMT1 and DNMT3a-genes implicated in DNA methylation-using peripheral blood leukocytes from Japanese patients with chronic schizophrenia and healthy controls. Additionally, using our previously acquired data, we explored the association between OCM-related factors and DNMT expression levels.Expression levels of DNMT1 and DNMT3a in 215 patients with chronic schizophrenia and 210 healthy controls were quantified using real-time PCR. The Mann-Whitney U test was used to compare the differences between two independent groups. Furthermore, Spearman's correlation analysis was conducted to investigate the relationships between DNMT genes` expression levels and OCM-related metabolites (blood folate, vitamin B6, and total homocysteine).The expression levels of DNMT1 and DNMT3a in peripheral leukocytes were significantly elevated in patients with chronic schizophrenia compared with controls (p = 1.4 × 10-6 and 2.9 × 10-3, respectively). DNMT1 mRNA expression levels exhibited a weak negative correlation with folate exclusively in the aggregated cohort (N = 425) (ρ = -0.16, adjusted q = 5.0 × 10-3), and DNMT3a mRNA expression levels showed a weak negative correlation with vitamin B6 alone in the combined group (ρ = -0.12, adjusted q = 0.03).These findings suggest a potential correlation between nutritional status and elevated expression of DNMT1 and DNMT3a in schizophrenia. Our findings contribute to the understanding of the epigenetic mechanisms associated with schizophrenia and highlight the need for further investigation of the relationships among gene expression, nutritional status, and psychiatric manifestations.
Toshiyuki Shirai, Satoshi Okazaki, Takaki Tanifuji, Shusuke Numata, Tomohiko Nakayama, Tomohiro Yoshida, Kentaro Mouri, Ikuo Otsuka, Noboru Hiroi and Akitoyo Hishimoto : Meta-analyses of epigenetic age acceleration and GrimAge components of schizophrenia or first-episode psychosis., Schizophrenia, 10, 1, 108, 2024.
(要約)
Schizophrenia is a common chronic psychiatric disorder that causes age-related dysfunction. The life expectancy in patients with schizophrenia is 10 years shorter than that in the general population because of the higher risk of other diseases, such as cardiovascular diseases. Aging studies based on DNA methylation status have received considerable attention. Several epigenetic age accelerations and predicted values of aging-related proteins (GrimAge and GrimAge2 components) have been analyzed in multiple diseases. However, no studies have investigated up to GrimAge and GrimAge2 components between patients with schizophrenia and controls. Therefore, we aimed to conduct multiple regression analyses to investigate the association between schizophrenia and epigenetic age accelerations and GrimAge and GrimAge2 components in seven cohorts. Furthermore, we included patients with first-episode psychosis whose illness duration was often shorter than schizophrenia in our analysis. We integrated these results with meta-analyses, noting the acceleration of GrimAge, GrimAge2, and DunedinPACE, and increase in adrenomedullin, beta-2 microglobulin, cystatin C, and plasminogen activation inhibitor-1 levels, in patients with schizophrenia or first-episode psychosis. These results corroborated the finding that patients with schizophrenia had an increased risk of diabetes, cardiovascular disease, and cognitive dysfunction from a biological perspective. Patients with schizophrenia and first-episode psychosis showed differences in the results when compared with controls. Such analyses may lead to the development of novel therapeutic targets to patients with schizophrenia or relevant diseases from the perspective of aging in the future.
Tomoki Ozaki, Yuta Yoshino, Ayumi Tachibana, Hideaki Shimizu, Takaaki Mori, Tomohiko Nakayama, Kazuaki Mawatari, Shusuke Numata, Junichi Iga, Akira Takahashi, Tetsuro Ohmori and Shu-ichi Ueno : Metabolomic alterations in the blood plasma of older adults with mild cognitive impairment and Alzheimer's disease (from the Nakayama Study)., Scientific Reports, 12, 1, 15205, 2022.
(要約)
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.
Yukiko Tomioka, Makoto Kinoshita, Hidehiro Umehara, Tomohiko Nakayama, Shinya Watanabe, Masahito Nakataki, Shusuke Numata and Tetsuro Ohmori : Association between serum folate levels and schizophrenia based on sex., Psychiatry and Clinical Neurosciences, 74, 9, 466-471, 2020.
(要約)
Our findings suggest that: (i) a low serum folate level may be associated with schizophrenia regardless of sex; and (ii) folate administration may be beneficial for the treatment of schizophrenia. In schizophrenic patients with low serum folate levels, folate administration might result in improvements in high tHcy and an increase in low vitamin B6 levels.
Tomohiko Nakayama, Hiroaki Edo, Yoshida Tomohiro, Matsumoto Yui, Shinya Watanabe, Masahito Nakataki, Shusuke Numata and Tetsuro Ohmori : Nortriptyline Therapy of Treatment-Resistant Depression: two case reports, The CINP 2021 Virtual World Congress, Online, Feb. 2021.