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Naomichi Okamoto,1 Keita Watanabe,2 LeHoa Ngyuyen,1,3 Atsuko Ikenouchi,1 Taro Kishi,4 Nakao Iwata,4 Shingo Kakeda,5 Yukunori Korogi,6 Reiji Yoshimura1 1Department of Psychiatry, University of Occupational and Environmental Health, Kitakyushu, Japan; 2Open Innovation Institute, Kyoto University, Kyoto, Japan; 3School of Medicine and Pharmacy, Vietnam National University, Hanoi, Vietnam; 4Department of Psychiatry, Fujita Medical University, Toyoake, Japan; 5Department of Radiology, Graduate School of Medicine, Hirosaki University, Hirosaki, Japan; 6Department of Radiology, University of Occupational and Environmental Health, Kitakyushu, JapanCorrespondence: Reiji YoshimuraDepartment of Psychiatry, University of Occupational and Environmental Health, Kitakyushu, Fukuoka 8078555, JapanTel +81 936917253Email yoshi621@med.uoeh-u.ac.jpPurpose: The kynurenine (KYN) pathway can directly or indirectly influence cerebral volume and neural integrity in patients with major depression (MD). The aim of the present study was to investigate neural network systems and the KYN pathway in patients with first-episode, drug-naïve MD.Patients and Methods: Twenty right-handed drug-naïve patients, with MD diagnosed using the Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition, Text Revision, Research Version, were included in this study. Magnetic resonance imaging scans and scores on the Hamilton Rating Scale for Depression were assessed, and serum sampling was performed prior to the start of pharmacological treatment. Image processing and data analysis were performed according to our recently published procedure. Serum metabolomes were measured in the cation and anion modes of CE-FTMS-based metabolome analysis.Results: We found that serum KYN levels were positively correlated with the Z-scores of the salience network but not with those of the central executive network or default mode network. No associations were observed between serum glutamate levels and the Z-score of any of the three networks.Conclusion: Our results indicate that serum KYN levels might affect the activity of the salience network in first-episode, drug-naïve patients with MD.Keywords: kynurenine, major depression, neural network, source-based morphometry

Asuka Katsuki,1 Shingo Kakeda,2 Keita Watanabe,2 Ryohei Igata,1 Yuka Otsuka,1 Taro Kishi,3 LeHoa Nguyen,1 Issei Ueda,2 Nakao Iwata,3 Yukunori Korogi,2 Reiji Yoshimura11Department of Psychiatry, University of Occupational and Environmental Health, Kitakyushu, Fukuoka 8078555, Japan; 2Department of Radiology, University of Occupational and Environmental Health, Kitakyushu, Fukuoka 8078555, Japan; 3Department of Psychiatry, Fujita Health University, Toyoake, Aichi 4701192, JapanCorrespondence: Reiji YoshimuraDepartment of Psychiatry, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, Fukuoka 8078555, JapanTel +81 93 691 7253Fax +81 93 692 4894Email yoshi621@med.uoeh-u.ac.jpObjective: Recently, a genome-wide association study successfully identified genetic variants associated with major depressive disorder (MDD). The study identified 17 independent single-nucleotide polymorphisms (SNPs) significantly associated with diagnosis of MDD. These SNPs were predicted to be enriched in genes that are expressed in the central nervous system and function in transcriptional regulation associated with neurodevelopment. The study aimed to investigate associations between 17 SNPs and brain morphometry using magnetic resonance imaging (MRI) in drug-naïve patients with MDD and healthy controls (HCs).Methods: Forty-seven patients with MDD and 42 HCs were included. All participants underwent T1-weighted structural MRI and genotyping. The genotype–diagnosis interactions associated with regional cortical thicknesses were evaluated using voxel-based morphometry for the 17 SNPs.Results: Regarding rs301806, an SNP in the RERE genomic regions, we found a significant difference in a genotype effect in the right-lateral orbitofrontal and postcentral lobes between diagnosis groups. After testing every possible diagnostic comparison, the genotype–diagnosis interaction in these areas revealed that the cortical thickness reductions in the MDD group relative to those in the HC group were significantly larger in T/T individuals than in C-carrier ones. For the other SNPs, no brain area was noted where a genotype effect significantly differed between the two groups.Conclusions: We found that a RERE gene SNP was associated with cortical thickness reductions in the right-lateral orbitofrontal and postcentral lobes in drug-naïve patients with MDD. The effects of RERE gene polymorphism and gene–environment interactions may exist in brain structures of patients with MDD.Keywords: single-nucleotide polymorphism, brain morphology, major depressive disorder, genome-wide association

Yuka Otsuka,1 Shingo Kakeda,2 Koichiro Sugimoto,2 Asuka Katsuki,1 Le Hoa Nguyen,1 Ryohei Igata,1 Keita Watanabe,2 Issei Ueda,2 Taro Kishi,3 Nakao Iwata,3 Yukunori Korogi,2 Reiji Yoshimura11Department of Psychiatry, University of Occupational and Environmental Health, Kitakyushu, Japan; 2Department of Radiology, University of Occupational and Environmental Health, Kitakyushu, Japan; 3Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, JapanPurpose: Compared with healthy subjects (HS), patients with major depressive disorder (MDD) exhibit volume differences that affect the volume changes in several areas such as the limbic, cortical, subcortical, and white matter. Catechol-O-methyltransferase (COMT) is a methylation enzyme that catalyzes endogenous catecholamines. The Val158Met polymorphism of COMT has been reported to affect the dopamine (DA) levels, which plays an important role in psychiatric diseases. However, the relationships among both DA levels, COMT genotype, and brain morphology are complicated and controversial. In previous studies that investigated the hippocampal subfields, the greatest brain abnormalities in MDD patients were observed in Cornu Ammonis (CA)1 and the subiculum, followed by that in CA2-3. We have prospectively demonstrated the relationship between the single-nucleotide polymorphism of the Val158Met COMT gene (rs4680) and the hippocampal subfields in drug-naive MDD patients.Patients and methods: In this study, we compared 27 MDD patients and 42 HS who were divided into groups based on their COMT genotype. The effects of the diagnosis, genotype, and genotype–diagnosis interaction related to CA1 and the subiculum volumes, as well as the whole-brain cortical thickness, were evaluated by performing a FreeSurfer statistical analysis of high-resolution magnetic resonance imaging (MRI) findings.Results: The results revealed that there was a statistically significant interaction between the effects of diagnosis and genotype on the right subiculum (a component of the hippocampus).Conclusion: This Val158Met COMT polymorphism may influence the subiculum volume in drug-naive, first-episode MDD patients.Keywords: major depressive disorder, COMT gene, brain morphology, hippocampal subfields volume, subiculum, surface-based morphometry

Shingo Kakeda,1 Keita Watanabe,1 Asuka Katsuki,2 Koichiro Sugimoto,1 Issei Ueda,1 Natsuki Igata,1 Taro Kishi,3 Nakao Iwata,3 Osamu Abe,4 Reiji Yoshimura,2 Yukunori Korogi1 1Department of Radiology, University of Occupational and Environmental Health, Kitakyushu, Japan; 2Department of Psychiatry, University of Occupational and Environmental Health, Kitakyushu, Japan; 3Department of Psychiatry, Fujita Health University, School of Medicine, Toyoake, Japan; 4Department of Radiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan Background: A genome-wide association study using megadata identified 17 single-nucleotide polymorphisms (SNPs) in candidate genes for major depressive disorder (MDD). These MDD susceptibility polymorphisms may affect white matter (WM) integrity. This study aimed to investigate the relationship between WM alterations and 17 SNPs in candidate genes for MDD in the first depressive episode of drug-naive MDD patients using a tract-based spatial statistics (TBSS) method. Methods: Thirty-five drug-naive MDD patients with a first depressive episode and 47 age- and sex-matched healthy subjects underwent diffusion tensor imaging scans and genotyping. The genotype–diagnosis interactions related to WM integrity were evaluated using TBSS for the 17 SNPs. Results: For the anterior thalamic radiation, cingulum, corticospinal tract, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, superior longitudinal fasciculus, uncinate fasciculus, forceps major, and forceps minor, the genotype effect significantly differed between diagnosis groups (P

Joji Nishimura,1 Shingo Kakeda,1 Osamu Abe,2 Reiji Yoshimura,3 Keita Watanabe,1 Naoki Goto,3 Hikaru Hori,3 Toru Sato,1 Hidemasa Takao,4 Hiroyuki Kabasawa,5 Jun Nakamura,3 Yukunori Korogi1 1Department of Radiology, University of Occupational and Environmental Health School of Medicine, Fukuoka, Japan; 2Department of Radiology, Graduate School of Medicine, Nihon University, Tokyo, Japan; 3Department of Psychiatry, University of Occupational and Environmental Health School of Medicine, Fukuoka, Japan; 4Department of Radiology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; 5MR Applied Science Laboratory Japan, GE Yokogawa Medical Systems, Hino-shi, Tokyo, Japan Abstract: The aims of this study are to determine how the interval changes of the brain structures in the early stage of first-episode schizophrenia relate to the interval changes in the clinical data, including the clinical symptoms of schizophrenia and catecholaminergic measures (plasma homovanillic acid [HVA] and 3-methoxy-4-hydroxyphenylglycol [MHPG]). Regional brain volumes and fractional anisotropy (FA)/mean diffusivity (MD) with diffusion tensor imaging (DTI) were measured at baseline and 6-month follow-up in a 3T magnetic resonance imaging (MRI) system in a cohort of 16 schizophrenic patients, who were in their first episode at the time of baseline MRI. At the time of baseline and follow-up MRI, all 16 patients underwent evaluations that included a psychopathological assessment (Positive and Negative Syndrome Scale [PANSS]) and peripheral catecholaminergic measures (plasma MHPG or HVA). For interval changes between baseline and follow-up MRI data (morphological change, MD, and FA), the correlation/regression analysis was performed as a series of single regression correlations in Statistical Parametric Mapping 5, with the interval changes in PANSS or plasma HVA and MHPG as the covariates of interest. Positive and inverse correlations contrasts were created, and in this preliminary analysis, a family-wise error-corrected threshold of P

Kenji Hayashi,1 Reiji Yoshimura,1 Shingo Kakeda,2 Taro Kishi,3 Osamu Abe,4 Wakako Umene-Nakano,1 Asuka Katsuki,1 Hikaru Hori,1 Atsuko Ikenouchi-Sugita,1 Keita Watanabe,2 Satoru Ide,2 Issei Ueda,2 Junji Moriya,2 Nakao Iwata,3 Yukunori Korogi,2 Marek Kubicki,5 Jun Nakamura1 1Department of Psychiatry, 2Department of Radiology, University of Occupational and Environmental Health, Kitakyushu, Japan; 3Department of Psychiatry, Fujita Health University, Toyoake, Japan; 4Department of Radiology, Nihon University School of Medicine, Tokyo, Japan; 5Psychiatry Neuroimaging Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA Abstract: We investigated the association between the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene, the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene, and white matter changes in patients with major depressive disorder (MDD) and healthy subjects using diffusion tensor imaging (DTI). We studied 30 patients with MDD (17 males and 13 females, with mean age ± standard deviation [SD] =44±12 years) and 30 sex- and age-matched healthy controls (17 males and 13 females, aged 44±13 years). Using DTI analysis with a tract-based spatial statistics (TBSS) approach, we investigated the differences in fractional anisotropy, radial diffusivity, and axial diffusivity distribution among the three groups (patients with the COMT gene Val158Met, those with the BDNF gene Val66Met, and the healthy subjects). In a voxel-wise-based group comparison, we found significant decreases in fractional anisotropy and axial diffusivity within the temporal lobe white matter in the Met-carriers with MDD compared with the controls (P

Naoki Goto1, Reiji Yoshimura1, Shingo Kakeda2, Joji Nishimura2, Junji Moriya2, Kenji Hayashi1, Asuka Katsuki1, Hikaru Hori1, Wakako Umene-Nakano1, Atsuko Ikenouchi-Sugita1, Yukunori Korogi2, Jun Nakamura11Department of Psychiatry, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, Japan; 2Department of Radiology, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, JapanObjective: To study the effects of treatment with atypical antipsychotic drugs on brain levels of glutamate plus glutamine in early-stage first-episode schizophrenia.Participants: Sixteen patients (eight males, eight females; aged 30 ± 11 years) completed the study.Methods: We used administered 6 months of atypical antipsychotic drugs and used proton magnetic resonance spectroscopy to evaluate the results.Results: We found that the administration of atypical antipsychotic drugs for 6 months decreased the glutamate plus glutamine/creatine ratio in the frontal lobe. These results suggest that the administration of atypical antipsychotic drugs for at least 6 months decreased glutamatergic neurotransmissions in the frontal lobe in early-stage first-episode schizophrenia, but there was no difference in frontal-lobe levels between patients and control subjects before administration.Conclusion: Taking these findings into account, the glutamatergic and GABAergic neurons are implicated in early-stage first-episode schizophrenia, but in complex ways.Keywords: Proton magnetic resonance spectroscopy, creatine, frontal lobe, parieto-occipital node, left basal ganglia

Visual hallucinations (VH) occur commonly in Lewy body disease (LBD), including Parkinson's disease (PD), PD with dementia, and dementia with Lewy bodies. We aimed to use phase difference enhanced imaging (PADRE) to assess structural abnormalities of optic radiation (OR) in patients with Lewy body disease (LBD) concomitant with VH. Firstly, two radiologists reviewed the OR appearances in healthy subjects (HS) on PADRE. Next, based on the OR abnormalities, two reviewers assessed the PADRE images from 18 HS and 38 and 110 patients with LBD, with and without VH, respectively, in a blinded manner. Finally, all patients with LBD without VH were eventually followed up for at least 5 years after magnetic resonance imaging to determine the appearance of VH. The radiologists identified three layers, namely external sagittal stratum, internal sagittal stratum, and tapetum, in OR on the PADRE in HS. Moreover, they were able to consensually define the OR as abnormal when the layers were obscured and the disappearance of the cranial side. The sensitivity/specificity of abnormal OR for each case was 68%/81% (LBD with VH vs. LBD without VH). Furthermore, VH appeared in 12 of the 21 (57%) patients with LBD and abnormal OR during the follow-up period. However, no patients without abnormal OR reported VH. Patients with LBD and VH demonstrated the abnormal OR. This, in turn, might be a useful marker to distinguish the patients with VH from those without VH and HS. Moreover, abnormal OR on PADRE may precede the appearance of VH in LBD., (© 2022. The Author(s).)

Background: Somatic cells differentiated from patient-specific human induced pluripotent stem cells (iPSCs) could be a useful tool in human cell-based disease research. Hermansky-Pudlak syndrome (HPS) is an autosomal recessive genetic disorder characterized by oculocutaneous albinism and a platelet dysfunction. HPS patients often suffer from lethal HPS associated interstitial pneumonia (HPSIP). Lung transplantation has been the only treatment for HPSIP. Lysosome-related organelles are impaired in HPS, thereby disrupting alveolar type 2 (AT2) cells with lamellar bodies. HPSIP lungs are characterized by enlarged lamellar bodies. Despite species differences between human and mouse in HPSIP, most studies have been conducted in mice since culturing human AT2 cells is difficult., Methods: We generated patient-specific iPSCs from patient-derived fibroblasts with the most common bi-allelic variant, c.1472_1487dup16, in HPS1 for modeling severe phenotypes of HPSIP. We then corrected the variant of patient-specific iPSCs using CRISPR-based microhomology-mediated end joining to obtain isogenic controls. The iPSCs were then differentiated into lung epithelial cells using two different lung organoid models, lung bud organoids (LBOs) and alveolar organoids (AOs), and explored the phenotypes contributing to the pathogenesis of HPSIP using transcriptomic and proteomic analyses., Results: The LBOs derived from patient-specific iPSCs successfully recapitulated the abnormalities in morphology and size. Proteomic analysis of AOs involving iPSC-derived AT2 cells and primary lung fibroblasts revealed mitochondrial dysfunction in HPS1 patient-specific alveolar epithelial cells. Further, giant lamellar bodies were recapitulated in patient-specific AT2 cells., Conclusions: The HPS1 patient-specific iPSCs and their gene-corrected counterparts generated in this study could be a new research tool for understanding the pathogenesis of HPSIP caused by HPS1 deficiency in humans., (© 2021. The Author(s).)

Extracorporeal membrane oxygenation is indispensable for critically severe COVID-19 patients. However, it would be inapplicable to patients with a rare blood type or blood transfusion refusal. In that case, severely conservative fluid management with the sacrifice of renal functions and hydrocortisone therapy should be considered for better oxygenation., Competing Interests: No author has a direct conflict of interest that is relevant to this study., (© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)