公募シンポジウム

公募シンポジウム酸化ストレスからみた自閉スペクトラム症

7月8日（土）　16:00-18:00　Room D 3SY⑦-1 臍帯血中エポキシ脂肪酸代謝が児の自閉症特性に与える影響 Cord blood epoxy fatty acid metabolism influences autistic symptoms in children 平井　孝治¹, 梅田　尚子¹, 土屋　賢治^2,4, 西村　倫子^2,4, 松崎　秀夫^3,4 1. 福井大学学術研究院医学系部門, 2. 浜松医科大学子どものこころの発達研究センター, 3. 福井大学子どものこころの発達研究センター, 4. 大阪大学連合小児発達学研究科 Takaharu Hirai¹, Naoko Umeda¹, J. Kenji Tsuchiya^2,4, Noriko Nishimura^2,4, Hideo Matsuzaki^3,4 1. Department of Psychiatric and Mental Health Nursing, School of Nursing, University of Fukui, 2. Research Center for Child Mental Development, Hamamatsu University School of Medicine, 3. Research Center for Child Mental Development, University of Fukui, 4. United Graduate School of Child Development, Hamamatsu University School of Medicine, Osaka University, Kanazawa University, Chiba University, and University of Fukui It has been suggested that abnormalities in lipid metabolism, represented by polyunsaturated fatty acids (PUFA), are involved in the pathogenesis of autism spectrum disorder (ASD). PUFA are metabolized to epoxy fatty acids by CYP450 enzymes and then to dihydroxy fatty acids by sEH enzymes, which are involved in inflammatory and anti-inflammatory roles. Previous studies have suggested that ASD-like behaviors exhibited by juvenile mice born from maternal exposure to the herbicide glyphosate are associated with increased sEH in the brain. We focused on the possibility that the inflammatory and anti-inflammatory effects associated with epoxy fatty acid metabolism of PUFA during the embryonic period may influence the ASD symptoms of the offspring. Therefore, the results of a study of 200 participants in the Hamamatsu Birth Cohort Study for Mothers and Children (HBC Study), which has been conducted since 2007, examining the association between the quantification of epoxy fatty acid metabolites with cord blood serum at birth and assessment scores of ASD symptoms in children at 6 years of age after birth, are presented in this symposium. In addition, as a future prospect based on our findings, we would also like to present our efforts to measure sEH enzyme activity, which is an essential factor for the epoxy fatty acid metabolic process.		7月8日（土）　16:00-18:00　Room D 3SY⑦-2 自閉スペクトラム症におけるグルタチオン、ミエリン、および脳機能ネットワーク Glutathione, myelin, and functional connectivity in autism spectrum disorder 岩渕　俊樹浜松医科大学　子どものこころの発達研究センター Toshiki Iwabuchi Research Center for Child Mental Development, Hamamatsu University School of Medicine, Hamamatsu, Japan Although the biological mechanisms of autism spectrum disorder (ASD) remain unclear, recent studies have implicated oxidative stress with ASD. Using 1H-MRS, we conducted an in vivo assessment of levels of glutathione (GSH), an important antioxidant in the brain. In the left temporoparietal junction (TPJ), we found an increased GSH level for 30 adults with ASD, compared to 27 typically developing (TD) adults. Next, by creating individual myelin maps, we found a significant group difference in the correlation between myelin in the middle frontal gyrus (MFG) and the GSH level in the left TPJ. Multivariate pattern analysis of resting-state fMRI data revealed that the whole-brain functional connectivity pattern from the left MFG was associated with myelin in the left MFG differently between groups. The association between emotion-recognition task performances and functional connectivity of the left MFG with the right occipital cortex was also significantly different between groups. Altogether, in the ASD group, our findings demonstrated an atypical association pattern among the GSH levels in the left TPJ, myelin in the left MFG, whole-brain functional connectivity from the left MFG, and emotion-recognition ability. These indicate compensatory neural mechanisms linking antioxidative GSH to behavioral characteristics in ASD.

7月8日（土）　16:00-18:00　Room D 3SY⑦-3 自閉スペクトラム症の前部帯状皮質のミトコンドリア活性低下：PET研究 Lower availability of mitochondrial complex I in the anterior cingulate cortex in autism spectrum disorder: PET study 加藤　康彦¹, 横倉　正倫^1,2, 岩渕　俊樹^2,3, 村山　千尋¹, 原田　妙子^2,3, 後藤　孝文¹, 玉山　大志¹, 亀野　陽亮^1,2, 和久田　智靖¹, 桑原　斉^1,2, ベナー　聖子¹, 千住　淳^2,3, 塚田　秀夫⁴, 西澤　貞彦⁵, 尾内　康臣^5,6, 山末　英典^1,2 1. 浜松医科大学精神医学講座, 2. 浜松医科大学連合小児発達学研究科, 3. 浜松医科大学子どものこころの発達研究センター, 4. 浜松ホトニクス　中央研究所, 5. 浜松光医学財団　浜松PET 診断センター, 6. 浜松医科大学生体機能イメージング研究室 Yasuhiko Kato¹, Masamichi Yokokura^1,2, Toshiki Iwabuchi^2,3, Chihiro Murayama¹, Taeko Harada^2,3, Takafumi Goto¹, Taishi Tamayama¹, Yosuke Kameno^1,2, Tomoyasu Wakuda¹, Hitoshi Kuwabara^1,2, Seico Benner¹, Atsushi Senju^2,3, Hideo Tsukada⁴, Sadahiko Nishizawa⁵, Yasuomi Ouchi^5,6, Hidenori Yamasue^1,2 1. Department of Psychiatry, Hamamatsu University School of Medicine, Hamamatsu, Japan, 2. United Graduate School of Child Development, Hamamatsu University School of Medicine, Hamamatsu, Japan, 3. Research Center for Child Mental Development, Hamamatsu University School of Medicine, Hamamatsu, Japan, 4. Central Research Laboratory, Hamamatsu Photonics KK, Hamamatsu, Japan, 5. Hamamatsu Medical Imaging Center, Hamamatsu Medical Photonics Foundation, Hamamatsu, Japan, 6. Department of Biofunctional Imaging, Hamamatsu University School of Medicine, Hamamatsu, Japan Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder whose core symptoms cannot be treated with any established medication. As its underlying pathophysiology is not yet fully understood, there is an urgent need to identify molecular targets in the brain for novel pharmacological treatments of ASD. Although mitochondrial dysfunction has been implicated in the pathophysiology of ASD in previous studies of postmortem brain or peripheral samples, no previous studies examined mitochondrial dysfunction in the living brains of subjects with ASD. We used positron emission tomography measurements with the radioligand [¹⁸F] BCPP-EF, which specifically binds to mitochondrial electron transport chain complex I (MC-I). The use of this radioligand enabled us to conduct an in vivo investigation of the topographical distribution of mitochondrial dysfunction. In this study, we demonstrated that psychotropics-free, high-functioning adult males with ASD had significantly decreased MC-I availability specifically in the anterior cingulate cortex compared with typically developed subjects matched for age, parental socio-economical background, and intelligence level. Moreover, decreased anterior cingulate MC-I availability significantly correlated with more severe sociocommunicational core symptom of ASD.		7月8日（土）　16:00-18:00　Room D 3SY⑦-4 ラット自閉症誘発モデルにおける抗酸化物質投与の効果 Effects of antioxidant treatment in a rat autism model 渋谷　淳, 岡野　拡東京農工大学大学院農学研究院獣医病理 Makoto Shibutani, Hiromu Okano Lab. of Vet. Pathol., Grad. Sch. of Agric., Tokyo Univ. of Agric. and Technol., Tokyo, Japan This study investigated the effects of immune activation at two different time windows of fetal and neonatal stages by administration of lipopolysaccharides (LPS) on hippocampal neurogenesis, oligodendrocyte (OL) differentiation and neurobehaviors in an LPS-induced rat autism model. To clarify how inflammatory and oxidative stress responses are involved in the neural deficits caused by immune activation, animals were subjected to antioxidant treatment continuously from fetal stage. For this purpose, we used α-glycosyl isoquercitrin (AGIQ), a rutin-derived quercetin antioxidant developed to increase bioavailability through oral intake. Immune activation of both time windows caused progressive disruption of hippocampal neurogenesis, aberrant neurobehaviors, and disruptive OL differentiation, showing different patterns between the two. Difference in the target population of GABAergic interneurons between the two was suggested to be dependent on the disruptive pattern of OL differentiation, and this difference may determine disruption pattern of neurogenesis. AGIQ treatment prior to LPS exposure restored most of the LPS-induced deficits, which may be due to antioxidant and anti-inflammatory effects. The effectiveness of AGIQ treatment may provide significant insights on the chemoprevention of autism spectrum disorder or schizophrenia caused by immune activation during development.

7月8日（土）　16:00-18:00　Room D 3SY⑦-5 自閉症成人に対する5-アミノレブリン酸リン酸塩の投与効果 The clinical effectiveness of 5-aminolevulinic acid phosphate on the core symptoms of autism spectrum disorder 松崎　秀夫¹ 1. 福井大学・子どものこころの発達研究センター, 2. 大阪大学大学院・連合小児発達学研究科 Hideo Matsuzaki¹ 1. Research Center for Child Mental Development, University of Fukui, Fukui, Japan, 2. United Graduate School of Child Development, Osaka University, Suita, Osaka Although mitochondria appear carry out a central role in autism spectrum disorder (ASD) pathophysiology by previous study, no study has been conducted to reveal whether mitochondrial function improvement is therapeutically useful for ASD. In this randomized, double-blind, placebo-controlled trial, using a within-subject crossover design in Japan, 74 ASD individuals (18-48 y.o.) were enrolled between April 2018 and March 2020. Participants were randomly assigned to a 12-week administration of 5-aminolevulinic acid phosphate (5-ALA) + sodium ferrous citrate (SFC) or placebo group. Finally, 49 participants were analyzed. We evaluated changes in their behavior and symptoms when 5-ALA+SFC was taken orally for 12 weeks in individuals with ASD aged 18 years or older. A 12-week oral administration of 1 capsule/day 5-ALA+SFC improved significantly the primary endpoint stereotyped behavior and stress peculiar to ASD compared with the placebo-term. On the other hands, oral administration of 6 capsules/day 5-ALA+SFC for 12 weeks had no effect to improve ASD symptoms. We also evaluated changes of mitochondrial function in peripheral lymphocyte when 5-ALA+SFC was taken orally for 12 weeks in individuals with ASD aged 18 years or older, but no significant difference was observed in the mitochondrial function of peripheral lymphocytes by 5-ALA+SFC administration for 12 weeks.