Kato Yasuhiko, Yokokura Masamichi, Iwabuchi Toshiki, Murayama Chihiro, Harada Taeko, Goto Takafumi, Tamayama Taishi, Kameno Yosuke, Wakuda Tomoyasu, Kuwabara Hitoshi, Benner Seico, Senju Atsushi, Tsukada Hideo, Nishizawa Sadahiko, Ouchi Yasuomi, Yamasue Hidenori
Department of Psychiatry (Kato, Yokokura, Murayama, Goto, Tamayama, Kameno, Wakuda, Kuwabara, Benner, Yamasue), United Graduate School of Child Development (Yokokura, Iwabuchi, Harada, Kameno, Kuwabara, Senju, Yamasue), Research Center for Child Mental Development (Iwabuchi, Harada, Senju), and Department of Biofunctional Imaging (Ouchi), Hamamatsu University School of Medicine, Hamamatsu, Japan; Central Research Laboratory, Hamamatsu Photonics K.K., Hamamatsu, Japan (Tsukada); Hamamatsu Medical Imaging Center, Hamamatsu Medical Photonics Foundation, Hamamatsu, Japan (Nishizawa, Ouchi).
Am J Psychiatry. 2023 Apr 1;180(4):277-284. doi: 10.1176/appi.ajp.22010014. Epub 2022 Sep 7.
Mitochondrial dysfunction has been implicated in the pathophysiology of autism spectrum disorder (ASD) in previous studies of postmortem brain or peripheral samples. The authors investigated whether and where mitochondrial dysfunction occurs in the living brains of individuals with ASD and to identify the clinical correlates of detected mitochondrial dysfunction.
This case-control study used positron emission tomography (PET) with 2--butyl-4-chloro-5-{6-[2-(2-[F]fluoroethoxy)-ethoxy]-pyridin-3-ylmethoxy}-2H-pyridazin-3-one ([F]BCPP-EF), a radioligand that binds to the mitochondrial electron transport chain complex I, to examine the topographical distribution of mitochondrial dysfunction in living brains of individuals with ASD. Twenty-three adult males with high-functioning ASD, with no psychiatric comorbidities and free of psychotropic medication, and 24 typically developed males with no psychiatric diagnoses, matched with the ASD group on age, parental socioeconomic background, and IQ, underwent [F]BCPP-EF PET measurements. Individuals with mitochondrial disease were excluded by clinical evaluation and blood tests for abnormalities in lactate and pyruvate levels.
Among the brain regions in which mitochondrial dysfunction has been reported in postmortem studies of autistic brains, participants with ASD had significantly decreased [F]BCPP-EF availability specifically in the anterior cingulate cortex compared with typically developed participants. The regional specificity was revealed by a significant interaction between diagnosis and brain regions. Moreover, the lower [F]BCPP-EF availability in the anterior cingulate cortex was significantly correlated with the more severe ASD core symptom of social communication deficits.
This study provides direct evidence to link in vivo brain mitochondrial dysfunction with ASD pathophysiology and its communicational deficits. The findings support the possibility that mitochondrial electron transport chain complex I is a novel therapeutic target for ASD core symptoms.
在先前对死后大脑或外周样本的研究中，线粒体功能障碍已被认为与自闭症谱系障碍（ASD）的病理生理学有关。作者研究了ASD个体的活体大脑中是否以及何处发生线粒体功能障碍，并确定检测到的线粒体功能障碍的临床相关性。
本病例对照研究使用正电子发射断层扫描（PET）和2-丁基-4-氯-5-{6-[2-(2-[F]氟乙氧基)-乙氧基]-吡啶-3-基甲氧基}-2H-哒嗪-3-酮（[F]BCPP-EF），一种与线粒体电子传递链复合体I结合的放射性配体，来检查ASD个体活体大脑中线粒体功能障碍的地形分布。23名无精神疾病合并症且未服用精神药物的高功能ASD成年男性，以及24名无精神疾病诊断、在年龄、父母社会经济背景和智商方面与ASD组匹配的发育正常男性，接受了[F]BCPP-EF PET测量。通过临床评估和血液检测乳酸和丙酮酸水平异常，排除了线粒体疾病患者。
在自闭症大脑的死后研究中报告有线粒体功能障碍的脑区中,与发育正常的参与者相比，ASD参与者在前扣带回皮质中[F]BCPP-EF的可用性显著降低。诊断和脑区之间的显著交互作用揭示了区域特异性。此外，前扣带回皮质中较低的[F]BCPP-EF可用性与更严重的ASD社交沟通缺陷核心症状显著相关。
本研究提供了直接证据，将体内脑线粒体功能障碍与ASD病理生理学及其沟通缺陷联系起来。这些发现支持线粒体电子传递链复合体I可能是ASD核心症状的新治疗靶点这一可能性。
