Faculty Profiles - ALEKSIC Branko

Papers - ALEKSIC Branko

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Exploration of coping styles in male patients with head and neck cancer: a prospective cohort study. Reviewed

Naohiro Sato, Hiroyuki Kimura, Yasunori Adachi, Naoki Nishio, Masahiko Ando, Tatsuya Tokura, Wataru Nagashima, Shinichi Kishi, Aya Yamauchi, Keizo Yoshida, Mariko Hiramatsu, Yasushi Fujimoto, Norio Ozaki

Nagoya journal of medical science Vol. 81 ( 2 ) page： 249 - 258 2019.5

Language：English Publishing type：Research paper (scientific journal)

Majority of head and neck cancer (HNC) patients are male, and more than 85% of patients with HNC have the habit of smoking and drinking. Due to the specific demographic characteristics, HNC patients are anticipated to have specific coping styles, affecting psychological distress, survival, and quality of life. We explored the subscales of the Mental Adjustment to Cancer (MAC) Scale in male patients with HNC, and then examined the correlation between revised subscales of the MAC scale and anxiety/depression. Participants were 150 male inpatients with HNC, and their demographic and medical data were obtained. Coping style was assessed by MAC scale. Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale. Out of 40 items in the original MAC scale, 19 items were excluded by factor analysis, and the remaining 21 items were divided into three factors: Negative Adjustment, Positive Adjustment, and Abandonment. Negative and Positive Adjustments were similar to the copings of mixed gender patients with heterogeneous cancers, and Abandonment was a new subscale specific to male patients with HNC. This subscale had a weak positive correlation with anxiety and depression. Male HNC patients revealed a specific coping style of Abandonment, related with psychological distress. We believe that an understanding of the Abandonment coping style revealed in our study will improve the psychological support offered to male patients with HNC.

DOI： 10.18999/nagjms.81.2.249

Proteomic analysis of lymphoblastoid cell lines from schizophrenic patients. Reviewed International journal

Akira Yoshimi, Shinnosuke Yamada, Shohko Kunimoto, Branko Aleksic, Akihiro Hirakawa, Mitsuki Ohashi, Yurie Matsumoto, Kazuhiro Hada, Norimichi Itoh, Yuko Arioka, Hiroki Kimura, Itaru Kushima, Yukako Nakamura, Tomoko Shiino, Daisuke Mori, Satoshi Tanaka, Shuko Hamada, Yukihiro Noda, Taku Nagai, Kiyofumi Yamada, Norio Ozaki

Translational psychiatry Vol. 9 ( 1 ) page： 126 - 126 2019.4

Language：English Publishing type：Research paper (scientific journal)

Although a number of studies have identified several convincing candidate genes or molecules, the pathophysiology of schizophrenia (SCZ) has not been completely elucidated. Therapeutic optimization based on pathophysiology should be performed as early as possible to improve functional outcomes and prognosis; to detect useful biomarkers for SCZ, which reflect pathophysiology and can be utilized for timely diagnosis and effective therapy. To explore biomarkers for SCZ, we employed fluorescence two-dimensional differential gel electrophoresis (2D-DIGE) of lymphoblastoid cell lines (LCLs) (1st sample set: 30 SCZ and 30 CON). Differentially expressed proteins were sequenced by liquid chromatography tandem-mass spectrometry (LC-MS/MS) and identified proteins were confirmed by western blotting (WB) (1st and 2nd sample set: 60 SCZ and 60 CON). Multivariate logistic regression analysis was performed to identify an optimal combination of biomarkers to create a prediction model for SCZ. Twenty protein spots were differentially expressed between SCZ and CON in 2D-DIGE analysis and 22 unique proteins were identified by LC-MS/MS. Differential expression of eight of 22 proteins was confirmed by WB. Among the eight candidate proteins (HSPA4L, MX1, GLRX3, UROD, MAPRE1, TBCB, IGHM, and GART), we successfully constructed logistic regression models comprised of 4- and 6-markers with good discriminative ability between SCZ and CON. In both WB and gene expression analysis of LCL, MX1 showed reproducibly significant associations. Moreover, Mx1 and its related proinflamatory genes (Mx2, Il1b, and Tnf) were also up-regulated in poly I:C-treated mice. Differentially expressed proteins might be associated with molecular pathophysiology of SCZ, including dysregulation of immunological reactions and potentially provide diagnostic and prognostic biomarkers.

DOI： 10.1038/s41398-019-0461-2

A NOVEL RARE VARIANT R292H IN RTN4R AFFECTS GROWTH CONE FORMATION AND POSSIBLY CONTRIBUTES TO SCHIZOPHRENIA SUSCEPTIBILITY

Kimura Hiroki, Ishizuka Kanako, Wang Chenyao, Kushima Itaru, Morikawa Mako, Uno Yota, Okada Takashi, Inanda Toshiya, Aleksic Branko, Mori Daisuke, Ozaki Norio

EUROPEAN NEUROPSYCHOPHARMACOLOGY Vol. 29 page： S1014 - S1014 2019

Rare Single-Nucleotide DAB1 Variants and their Contribution to Schizophrenia and Autism Spectrum Disorder Susceptibility. Reviewed

Nawa Y, Kimura H, Kato H, Toyama M, Furuta S, Yu Y, Ishizuka K, Kushima I, Aleksic B, Arioka Y, Mori D, Morikawa M, Okada T, Toshiya I, Ikeda M, Iwata N, Suzuki M, Okahisa Y, Egawa J, Someya T, Nishimura F, Sasaki T, Ozaki N

Scientific Reports Vol. in press 2019

Stable factor structure of the Edinburgh Postnatal Depression Scale during the whole peripartum period: Results from a Japanese prospective cohort study. Reviewed International journal

Chika Kubota, Toshiya Inada, Yukako Nakamura, Tomoko Shiino, Masahiko Ando, Branko Aleksic, Aya Yamauchi, Mako Morikawa, Takashi Okada, Masako Ohara, Maya Sato, Satomi Murase, Setsuko Goto, Atsuko Kanai, Norio Ozaki

Scientific reports Vol. 8 ( 1 ) page： 17659 - 17659 2018.12

Language：English Publishing type：Research paper (scientific journal)

Early detection of perinatal depression is an urgent issue. Our study aimed to examine the construct validity and factor structure of the Japanese version of the Edinburgh Postnatal Depression Scale (EPDS) from a prospective cohort study from pregnancy to postpartum. A total of 1075 women completed all items of the EPDS at four time points: early pregnancy, late pregnancy, 5 days postpartum and 1 month postpartum. The participants were randomly divided into two sample sets. The first sample set (n = 304) was used for exploratory factor analysis, and the second sample set (n = 771) was used for confirmatory factor analysis. As a result, the Cronbach's alpha coefficients of the EPDS items were 0.762, 0.740, 0.765 and 0.772 at the four time points. From the confirmatory factor analysis of the EPDS in a sample set of Japanese women from pregnancy to postpartum, the following three factors were detected: depression (items 7, 9), anxiety (items 4, 5) and anhedonia (items 1, 2). In conclusion, the EPDS is a useful rating scale, and its factor structure is consistently stable during the whole peripartum period.

DOI： 10.1038/s41598-018-36101-z

Dysregulation of schizophrenia-related aquaporin 3 through disruption of paranode influences neuronal viability. International journal

Kazuo Kunisawa, Takeshi Shimizu, Itaru Kushima, Branko Aleksic, Daisuke Mori, Yasuyuki Osanai, Kenta Kobayashi, Anna M Taylor, Manzoor A Bhat, Akiko Hayashi, Hiroko Baba, Norio Ozaki, Kazuhiro Ikenaka

Journal of neurochemistry Vol. 147 ( 3 ) page： 395 - 408 2018.11

Language：English Publishing type：Research paper (scientific journal)

Myelinated axons segregate the axonal membrane into four defined regions: the node of Ranvier, paranode, juxtaparanode, and internode. The paranodal junction consists of specific component proteins, such as neurofascin155 (NF155) on the glial side, and Caspr and Contactin on the axonal side. Although paranodal junctions are thought to play crucial roles in rapid saltatory conduction and nodal assembly, the role of their interaction with neurons is not fully understood. In a previous study, conditional NF155 knockout in oligodendrocytes led to disorganization of the paranodal junctions. To examine if disruption of paranodal junctions affects neuronal gene expression, we prepared total RNA from the retina of NF155 conditional knockout, and performed expression analysis. We found that the expression level of 433 genes changed in response to paranodal junction ablation. Interestingly, expression of aquaporin 3 (AQP3) was significantly reduced in NF155 conditional knockout mice, but not in cerebroside sulfotransferase knockout (CST-KO) mice, whose paranodes are not originally formed during development. Copy number variations have an important role in the etiology of schizophrenia (SCZ). We observed rare duplications of AQP3 in SCZ patients, suggesting a correlation between abnormal AQP3 expression and SCZ. To determine if AQP3 over-expression in NF155 conditional knockout mice influences neuronal function, we performed adeno-associated virus (AAV)-mediated over-expression of AQP3 in the motor cortex of mice and found a significant increase in caspase 3-dependent neuronal apoptosis in AQP3-transduced cells. This study may provide new insights into therapeutic approaches for SCZ by regulating AQP3 expression, which is associated with paranodal disruption.

DOI： 10.1111/jnc.14553

Assessment of a glyoxalase I frameshift variant, p.P122fs, in Japanese patients with schizophrenia. Reviewed International journal

Kanako Ishizuka, Hiroki Kimura, Itaru Kushima, Toshiya Inada, Yuko Okahisa, Masashi Ikeda, Nakao Iwata, Daisuke Mori, Branko Aleksic, Norio Ozaki

Psychiatric genetics Vol. 28 ( 5 ) page： 90 - 93 2018.10

Language：English Publishing type：Research paper (scientific journal)

Enhanced carbonyl stress has been observed in a subgroup of patients with schizophrenia. Glyoxalase I, which is encoded by GLO1, is an enzyme that protects against carbonyl stress. In this study, we focused on the association between rare genetic variants of GLO1 and schizophrenia. First, we identified one heterozygous frameshift variant, p.P122fs, in 370 Japanese schizophrenia cases with allele frequencies of up to 1% by exon-targeted mutation screening of GLO1. We then performed an association analysis on 1282 cases and 1764 controls with this variant. The variant was found in three cases and eight controls. There was no statistically significant association between p.P122fs in GLO1 and schizophrenia (P=0.25). This frameshift variant in GLO1 might occur at near-polymorphic frequencies in the Japanese population, although further investigations using larger samples and biological analyses are needed to exclude the possibility of a low-penetrance genetic risk associated with this variant.

DOI： 10.1097/YPG.0000000000000204

Impact of perceived rearing and social support on bonding failure and depression among mothers: A longitudinal study of pregnant women. Reviewed International journal

Masako Ohara, Masahiro Nakatochi, Takashi Okada, Branko Aleksic, Yukako Nakamura, Tomoko Shiino, Aya Yamauchi, Chika Kubota, Mako Morikawa, Satomi Murase, Setsuko Goto, Atsuko Kanai, Ryuji Kato, Masahiko Ando, Norio Ozaki

Journal of psychiatric research Vol. 105 page： 71 - 77 2018.10

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Although previous studies have reported associations between bonding failure, depression, social support among mothers, and perceived rearing, the causal relationships remain unclear. METHODS: A total of 855 women (mean age, 32.4 ± 4.4 years) completed the Mother-Infant Bonding Questionnaire (MIBQ), the Edinburgh Postnatal Depression Scale (EPDS), the Japanese version of the Social Support Questionnaire, and the Parental Bonding Instrument in early pregnancy before week 25 (T1) and at 1 month after delivery (T2). We created a path model to clarify the causal relationships between perinatal bonding failure, depression, social support, and perceived rearing during pregnancy and at 1 month after delivery. The model was tested using structural equation modeling. RESULTS: Our recursive model showed acceptable fit (chi-squared statistic/degree of freedom = 2.1, comparative fit index = 0.98, root mean square error of approximation = 0.04). It was revealed that: (1) at T1, higher overprotection significantly predicted MIBQ scores; (2) at T1, poorer social support significantly predicted both MIBQ and EPDS scores; and (3) at T1, both MIBQ and EPDS scores significantly predicted respective scores at T2. CONCLUSIONS: These results showed that bonding failure in the postpartum period was significantly influenced by mothers' own perceived rearing and social support during pregnancy. In addition, depression in the postpartum period was strongly influenced by social support during pregnancy. These findings suggest that psychosocial interventions that focus on both mothers' recollections of their own upbringing and social support during pregnancy are effective for preventing bonding failure and depression in the postpartum period.

DOI： 10.1016/j.jpsychires.2018.09.001

The Current Status and Future Prospects of Oncolytic Viruses in Clinical Trials against Melanoma, Glioma, Pancreatic, and Breast Cancers. International journal

Ibrahim Ragab Eissa, Itzel Bustos-Villalobos, Toru Ichinose, Shigeru Matsumura, Yoshinori Naoe, Noriyuki Miyajima, Daishi Morimoto, Nobuaki Mukoyama, Wu Zhiwen, Maki Tanaka, Hitoki Hasegawa, Seiji Sumigama, Branko Aleksic, Yasuhiro Kodera, Hideki Kasuya

Cancers Vol. 10 ( 10 ) page： 356 2018.10

Language：English Publishing type：Research paper (scientific journal)

Oncolytic viral therapy has been accepted as a standard immunotherapy since talimogene laherparepvec (T-VEC, Imlygic®) was approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for melanoma treatment in 2015. Various oncolytic viruses (OVs), such as HF10 (Canerpaturev-C-REV) and CVA21 (CAVATAK), are now actively being developed in phase II as monotherapies, or in combination with immune checkpoint inhibitors against melanoma. Moreover, in glioma, several OVs have clearly demonstrated both safety and a promising efficacy in the phase I clinical trials. Additionally, the safety of several OVs, such as pelareorep (Reolysin®), proved their safety and efficacy in combination with paclitaxel in breast cancer patients, but the outcomes of OVs as monotherapy against breast cancer have not provided a clear therapeutic strategy for OVs. The clinical trials of OVs against pancreatic cancer have not yet demonstrated efficacy as either monotherapy or as part of combination therapy. However, there are several oncolytic viruses that have successfully proved their efficacy in different preclinical models. In this review, we mainly focused on the oncolytic viruses that transitioned into clinical trials against melanoma, glioma, pancreatic, and breast cancers. Hence, we described the current status and future prospects of OVs clinical trials against melanoma, glioma, pancreatic, and breast cancers.

DOI： 10.3390/cancers10100356

Comparative Analyses of Copy-Number Variation in Autism Spectrum Disorder and Schizophrenia Reveal Etiological Overlap and Biological Insights. Reviewed International journal

Itaru Kushima, Branko Aleksic, Masahiro Nakatochi, Teppei Shimamura, Takashi Okada, Yota Uno, Mako Morikawa, Kanako Ishizuka, Tomoko Shiino, Hiroki Kimura, Yuko Arioka, Akira Yoshimi, Yuto Takasaki, Yanjie Yu, Yukako Nakamura, Maeri Yamamoto, Tetsuya Iidaka, Shuji Iritani, Toshiya Inada, Nanayo Ogawa, Emiko Shishido, Youta Torii, Naoko Kawano, Yutaka Omura, Toru Yoshikawa, Tokio Uchiyama, Toshimichi Yamamoto, Masashi Ikeda, Ryota Hashimoto, Hidenaga Yamamori, Yuka Yasuda, Toshiyuki Someya, Yuichiro Watanabe, Jun Egawa, Ayako Nunokawa, Masanari Itokawa, Makoto Arai, Mitsuhiro Miyashita, Akiko Kobori, Michio Suzuki, Tsutomu Takahashi, Masahide Usami, Masaki Kodaira, Kyota Watanabe, Tsukasa Sasaki, Hitoshi Kuwabara, Mamoru Tochigi, Fumichika Nishimura, Hidenori Yamasue, Yosuke Eriguchi, Seico Benner, Masaki Kojima, Walid Yassin, Toshio Munesue, Shigeru Yokoyama, Ryo Kimura, Yasuko Funabiki, Hirotaka Kosaka, Makoto Ishitobi, Tetsuro Ohmori, Shusuke Numata, Takeo Yoshikawa, Tomoko Toyota, Kazuhiro Yamakawa, Toshimitsu Suzuki, Yushi Inoue, Kentaro Nakaoka, Yu-Ichi Goto, Masumi Inagaki, Naoki Hashimoto, Ichiro Kusumi, Shuraku Son, Toshiya Murai, Tempei Ikegame, Naohiro Okada, Kiyoto Kasai, Shohko Kunimoto, Daisuke Mori, Nakao Iwata, Norio Ozaki

Cell reports Vol. 24 ( 11 ) page： 2838 - 2856 2018.9

Language：English Publishing type：Research paper (scientific journal)

Compelling evidence in Caucasian populations suggests a role for copy-number variations (CNVs) in autism spectrum disorder (ASD) and schizophrenia (SCZ). We analyzed 1,108 ASD cases, 2,458 SCZ cases, and 2,095 controls in a Japanese population and confirmed an increased burden of rare exonic CNVs in both disorders. Clinically significant (or pathogenic) CNVs, including those at 29 loci common to both disorders, were found in about 8% of ASD and SCZ cases, which was significantly higher than in controls. Phenotypic analysis revealed an association between clinically significant CNVs and intellectual disability. Gene set analysis showed significant overlap of biological pathways in both disorders including oxidative stress response, lipid metabolism/modification, and genomic integrity. Finally, based on bioinformatics analysis, we identified multiple disease-relevant genes in eight well-known ASD/SCZ-associated CNV loci (e.g., 22q11.2, 3q29). Our findings suggest an etiological overlap of ASD and SCZ and provide biological insights into these disorders.

DOI： 10.1016/j.celrep.2018.08.022

Aberrant functional connectivity between the thalamus and visual cortex is related to attentional impairment in schizophrenia. Reviewed International journal

Maeri Yamamoto, Itaru Kushima, Ryohei Suzuki, Aleksic Branko, Naoko Kawano, Toshiya Inada, Tetsuya Iidaka, Norio Ozaki

Psychiatry research. Neuroimaging Vol. 278 page： 35 - 41 2018.8

Language：English Publishing type：Research paper (scientific journal)

Resting-state (rs) functional magnetic resonance imaging (fMRI) studies have revealed dysfunctional thalamocortical functional connectivity (FC) in schizophrenia. However, the relationship between thalamocortical FC and cognitive impairment has not been thoroughly investigated. We hypothesized that aberrant thalamocortical FC is related to attention deficits in schizophrenia. Thirty-eight patients with schizophrenia and 38 matched healthy controls underwent rs-fMRI and task fMRI while performing a Flanker task. We observed decreased left thalamic activation in patients with schizophrenia using task fMRI to determine the thalamic seed. A seed-based analysis using this seed was performed in the whole brain to assess differences in thalamocortical FC between the groups. Significantly worse performance was observed in the patient group. The rs-fMRI analysis revealed significantly increased FC between the left thalamus seed and the occipital cortices/postcentral gyri in patients when compared to controls. In the patient group, significant positive correlations were observed between the degree of FC from the left thalamus to the bilateral occipital gyri, which correspond to the visual cortex, and the Flanker effect. No significant correlation was detected in the control group. These results indicate that aberrant FC between the left thalamus and the visual cortex is related to attention deficits in schizophrenia.

DOI： 10.1016/j.pscychresns.2018.06.007

Genetic and animal model analyses reveal the pathogenic role of a novel deletion of RELN in schizophrenia. Reviewed International journal

Akira Sobue, Itaru Kushima, Taku Nagai, Wei Shan, Takao Kohno, Branko Aleksic, Yuki Aoyama, Daisuke Mori, Yuko Arioka, Naoko Kawano, Maeri Yamamoto, Mitsuharu Hattori, Toshitaka Nabeshima, Kiyofumi Yamada, Norio Ozaki

Scientific reports Vol. 8 ( 1 ) page： 13046 - 13046 2018.8

Language：English Publishing type：Research paper (scientific journal)

Reelin protein (RELN), an extracellular matrix protein, plays multiple roles that range from embryonic neuronal migration to spine formation in the adult brain. Results from genetic studies have suggested that RELN is associated with the risk of psychiatric disorders, including schizophrenia (SCZ). We previously identified a novel exonic deletion of RELN in a patient with SCZ. High-resolution copy number variation analysis revealed that this deletion included exons 52 to 58, which truncated the RELN in a similar manner to the Reln Orleans mutation (Relnrl-Orl). We examined the clinical features of this patient and confirmed a decreased serum level of RELN. To elucidate the pathophysiological role of the exonic deletion of RELN in SCZ, we conducted behavioral and neurochemical analyses using heterozygous Relnrl-Orl/+ mice. These mice exhibited abnormalities in anxiety, social behavior, and motor learning; the deficits in motor learning were ameliorated by antipsychotics. Methamphetamine-induced hyperactivity and dopamine release were significantly reduced in the Relnrl-Orl/+ mice. In addition, the levels of GABAergic markers were decreased in the brain of these mice. Taken together, our results suggest that the exonic deletion of RELN plays a pathological role, implicating functional changes in the dopaminergic and GABAergic systems, in the pathophysiology of SCZ.

DOI： 10.1038/s41598-018-31390-w

Postpartum depression among women in Nagoya indirectly exposed to the Great East Japan Earthquake. Reviewed International journal

Chika Kubota, Takashi Okada, Mako Morikawa, Yukako Nakamura, Aya Yamauchi, Masahiko Ando, Tomoko Shiino, Masako Ohara, Satomi Murase, Setsuko Goto, Atsuko Kanai, Tomoko Masuda, Branko Aleksic, Norio Ozaki

Scientific reports Vol. 8 ( 1 ) page： 11624 - 11624 2018.8

Language：English Publishing type：Research paper (scientific journal)

This study aimed to assess the situation of postpartum depression and maternal bonding in Nagoya, a city distant from the epicenter of the Great East Japan Earthquake that occurred on March 11, 2011. Among the participants at 1 month after childbirth between March 11, 2010 and March 10, 2013 (n = 188), 152 fully responded to the Edinburgh Postnatal Depression Scale (EPDS) and Mother-Infant Bonding Questionnaire (MIBQ). They were divided into pre-quake (n = 58), and 0-6, 6-12, 12-18, and 18-24 months after the earthquake groups (n = 20, 26, 29, and 19, respectively). The rate of mothers who scored above the cutoff point for the EPDS increased from 12.1% in the pre-quake to 35.0% in the 0-6 months group (p = 0.022). The EPDS total and anxiety subscale scores (mean ± standard error) were also significantly different between the pre-quake and 0-6 months after the earthquake groups (4.45 ± 0.50 vs. 7.95 ± 1.47, p = 0.024; 2.16 ± 0.26 vs. 3.65 ± 0.57, p = 0.021, respectively). The EPDS total and anxiety scores were the highest for the 0-6 months group, followed by the 6-12, 12-18, 18-24 months groups (p = 0.019, p = 0.022). MIBQ scores did not differ between the pre-quake and 0-6 months groups. Depressive symptoms, mainly explained by anxiety, increased after the earthquake with no changes in maternal bonding.

DOI： 10.1038/s41598-018-30065-w

Single-cell trajectory analysis of human homogenous neurons carrying a rare RELN variant. Reviewed International journal

Yuko Arioka, Emiko Shishido, Hisako Kubo, Itaru Kushima, Akira Yoshimi, Hiroki Kimura, Kanako Ishizuka, Branko Aleksic, Takuji Maeda, Mitsuru Ishikawa, Naoko Kuzumaki, Hideyuki Okano, Daisuke Mori, Norio Ozaki

Translational psychiatry Vol. 8 ( 1 ) page： 129 - 129 2018.7

Language：English Publishing type：Research paper (scientific journal)

Reelin is a protein encoded by the RELN gene that controls neuronal migration in the developing brain. Human genetic studies suggest that rare RELN variants confer susceptibility to mental disorders such as schizophrenia. However, it remains unknown what effects rare RELN variants have on human neuronal cells. To this end, the analysis of human neuronal dynamics at the single-cell level is necessary. In this study, we generated human-induced pluripotent stem cells carrying a rare RELN variant (RELN-del) using targeted genome editing; cells were further differentiated into highly homogeneous dopaminergic neurons. Our results indicated that RELN-del triggered an impaired reelin signal and decreased the expression levels of genes relevant for cell movement in human neurons. Single-cell trajectory analysis revealed that control neurons possessed directional migration even in vitro, while RELN-del neurons demonstrated a wandering type of migration. We further confirmed these phenotypes in neurons derived from a patient carrying the congenital RELN-del. To our knowledge, this is the first report of the biological significance of a rare RELN variant in human neurons based on individual neuron dynamics. Collectively, our approach should be useful for studying reelin function and evaluating mental disorder susceptibility, focusing on individual human neuronal migration.

DOI： 10.1038/s41398-018-0177-8

Driving performance of stable outpatients with depression undergoing real-world treatment. International journal

Akemi Miyata, Kunihiro Iwamoto, Naoko Kawano, Branko Aleksic, Masahiko Ando, Kazutoshi Ebe, Kiyoshi Fujita, Motonori Yokoyama, Tsuyoshi Akiyama, Yoshio Igarashi, Norio Ozaki

Psychiatry and clinical neurosciences Vol. 72 ( 6 ) page： 399 - 408 2018.6

Language：English Publishing type：Research paper (scientific journal)

AIM: Although the effects of psychotropics on driving ability have received much attention, little research is available on driving performance of stable outpatients with depression undergoing real-world treatment. This observational study investigated driving performance, cognitive functions, and depressive symptomatology of partly remitted outpatients with depression under daily-practice psychopharmacologic treatment. METHODS: Seventy stable outpatients with depression and 67 healthy volunteers were enrolled. Patients' prescriptions were not controlled in order to capture the real-world treatment environment. Participants underwent three driving tasks - road-tracking, car-following, and harsh-braking - using a driving simulator, and three cognitive tasks - Continuous Performance Test, Wisconsin Card Sorting Test, and Trail-Making Test. The Symptom Assessment Scale - Structured Interview Guide for the Hamilton Depression Rating Scale, Beck Depression Inventory-II, Social Adaptation Self-Evaluation Scale, and Stanford Sleepiness Scale were also completed. RESULTS: Although many patients received various pharmacologic treatments, there were no significant differences in the three driving tasks between outpatients with depression and healthy controls. Difficulty of maintaining set in the Wisconsin Card Sorting Test was significantly increased in patients with depression. Results on the Social Adaptation Self-Evaluation Scale were significantly associated with road-tracking and car-following performance, in contrast to results on the Hamilton Depression Rating Scale and the Beck Depression Inventory-II. CONCLUSION: We conclude that partly remitted depressive patients under steady-state pharmacologic treatment do not differ from healthy controls with respect to driving performance, which seems to be more affected by psychosocial functioning than by pharmacologic agents. This, however, should be investigated systematically in an off/on study.

DOI： 10.1111/pcn.12648

Possible involvement of a cell adhesion molecule, Migfilin, in brain development and pathogenesis of autism spectrum disorders. International journal

Kanako Ishizuka, Hidenori Tabata, Hidenori Ito, Itaru Kushima, Mariko Noda, Akira Yoshimi, Masahide Usami, Kyota Watanabe, Mako Morikawa, Yota Uno, Takashi Okada, Daisuke Mori, Branko Aleksic, Norio Ozaki, Koh-Ichi Nagata

Journal of neuroscience research Vol. 96 ( 5 ) page： 789 - 802 2018.5

Language：English Publishing type：Research paper (scientific journal)

Migfilin, encoded by FBLIM1 at the 1p36 locus, is a multi-domain adaptor protein essential for various cellular processes such as cell morphology and migration. Small deletions and duplications at the 1p36 locus, monosomy of which results in neurodevelopmental disorders and multiple congenital anomalies, have also been identified in patients with autism spectrum disorder (ASD). However, the impact of FBLIM1, the gene within 1p36, on the pathogenesis of ASD is unknown. In this study, we performed morphological analyses of migfilin to elucidate its role in brain development. Migfilin was detected specifically in the embryonic and perinatal stages of the mouse brain. Either silencing or overexpression of migfilin in embryos following in utero electroporation disrupted Neocortical neuronal migration. Additionally, neurite elongation was impaired when migfilin was silenced in cultured mouse hippocampal neurons. We then screened FBLIM1 for rare exonic deletions/duplications in 549 Japanese ASD patients and 824 controls, detecting one case of ASD and intellectual delay that harbored a 26-kb deletion at 1p36.21 that solely included the C-terminal exon of FBLIM1. The FBLIM1 mRNA expression level in this case was reduced compared to levels in individuals without FBLIM1 deletion. Our findings indicate that tightly regulated expression of migfilin is essential for neuronal development and that FBLIM1 disruption may be related to the phenotypes associated with ASD and related neurodevelopmental disorders.

DOI： 10.1002/jnr.24194

Copy Number Variant in the Region of Adenosine Kinase (ADK) and Its Possible Contribution to Schizophrenia Susceptibility. International journal

Hiroki Kimura, Itaru Kushima, Akira Yohimi, Branko Aleksic, Norio Ozaki

The international journal of neuropsychopharmacology Vol. 21 ( 5 ) page： 405 - 409 2018.5

Language：English Publishing type：Research paper (scientific journal)

Background: Adenosine kinase (ADK) is supposed to be a schizophrenia susceptibility gene based on the findings that ADK is an enzyme that catalyzes transfer of the gamma-phosphate from ATP to adenosine, which interacts with dopamine and glutamate neurotransmitters. However, no reports of schizophrenia cases with loss of function variants in the ADK region have been published. In our previous study investigating copy number variants in schizophrenia, we detected a copy number variant in the ADK region in 1 of 1699 schizophrenia patients. Methods: We validated the ADK deletion by determining the breakpoint. Then, we compared the relative expression of ADK in 32 schizophrenia patients, including a schizophrenia patient with deletion of ADK, with 29 healthy controls using lymphoblastoid cell lines. Furthermore, we evaluated the clinical phenotypes of the schizophrenia with ADK deletion. Result: We validated the copy number variants with Sanger sequencing and predicted that this copy number variant results in loss of function of ADK. Furthermore, expression analysis of mRNA from peripheral blood in this schizophrenia patient with the ADK deletion showed an extremely low level of ADK. Here we describe a case report of a patient with ADK deletion with phenotypes (schizophrenia, parkinsonism, epilepsy) that are predicted when ADK function is disrupted. Conclusion: Considering that the patient had a low ADK mRNA level and showed a phenotype that may be related to ADK deficiency, the copy number variants in the region of ADK may be strongly related to the phenotypes described here, such as schizophrenia, Parkinsonism, and epilepsy.

DOI： 10.1093/ijnp/pyx103

Whole exome sequencing of 14 schizophrenia multiplex families in Japan Reviewed International journal

Toyama Miho, Takasaki Yuto, Aleksic Branko, Ogi Tomoo, Ozaki Norio

HUMAN GENOMICS Vol. 12 2018.3

Whole exome sequencing of 14 schizophrenia multiplex families in Japan Reviewed International journal

Toyama Miho, Takasaki Yuto, Aleksic Branko, Ogi Tomoo, Ozaki Norio

HUMAN GENOMICS Vol. 12 2018.3

Issues on the diagnosis and etiopathogenesis of mood disorders: reconsidering DSM-5 Reviewed International journal

Kazuyoshi Ogasawara, Yukako Nakamura, Hiroyuki Kimura, Branko Aleksic, Norio Ozaki

Journal of Neural Transmission Vol. 125 ( 2 ) page： 211 - 222 2018.2

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer-Verlag Wien

The authors present a narrative review from the diagnostic and nosologic viewpoints of mood disorders (bipolar and depressive ones) by revisiting the revision from the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders, Text Revision to DSM-5, including the following: the separation of the bipolar and depressive sections
the addition of increased energy and continuation of symptoms to the hypo/manic criteria
the elimination of mixed episodes
the creation of new categories and specifiers (“other specified bipolar and related disorder”, “disruptive mood dysregulation disorder”, “with anxious distress”, “with mixed features”, “with peripartum onset”)
the categorization of hypo/manic episodes during antidepressant treatment into bipolar disorder
the elimination of the “bereavement exclusion”
the ambiguous separation between bipolar I and II
the insufficient distinction between “other specified bipolar and related disorders” and major depressive disorder
the differentiation regarding borderline personality disorder
agitation
premenstrual dysphoric disorder
and society and psychiatry. Through this analysis, we point out both the achievements and limitations of DSM-5. In addition, to examine the future direction of psychiatry, we introduce our cohort study regarding maternal depression and an outline of the National Institute of Mental Health’s Research Domain Criteria project in the US. Finally, we advocate the importance of elucidating etiopathogeneses by starting from or going beyond the DSM operational diagnostic system, which has shown great efficacy.

DOI： 10.1007/s00702-017-1828-2

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12
13