BRAIN SEROTONIN SYNTHESIS IN AUTISM

自闭症患者的大脑血清素合成

• 批准号: 2703874
• 负责人: DIANE C CHUGANI
• 金额: $ 25.06万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-15 至 2001-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2703874
• 关键词: autism; child (0-11); clinical research; epilepsy; family genetics; human subject; neuroanatomy; neurochemistry; neurotransmitter biosynthesis; positron emission tomography; serotonin

Autism is a devastating neurodevelopmental disorder characterized by a spectrum of abnormal behaviors including profound impairment in social interaction and communication, restrictive repetitive and stereotyped patterns of behavior, interests, and activities, as well as stereotypic motor abnormalities. Studies investigating alterations of neuro- transmitters in blood of autistic patients have consistently found increased platelet serotonin in approximately one-third to one-half of autistic patients. Studies of the serotonin metabolite 5-HIAA in cerebrospinal fluid, however, have failed to demonstrate consistent abnormalities of central serotonergic tone. Previously, no method for direct in vivo measurement of serotonin synthesis in humans was available, and only indirect and relatively insensitive measures could be made. Alpha[C-11]-Methyl-L-tryptophan has been developed as a tracer for serotonin synthesis with positron emission tomography (PET) and now allows a direct in vivo measurement of serotonin synthesis in humans. Using this technique, we have preliminary data demonstrating alteration in the whole brain serotonin synthesis in autistic children, as compared to their siblings aged 8-14 years or children with epilepsy aged 2-12 years. Furthermore, we have found focal differences between autistic boys and their siblings. Asymmetries of serotonin synthesis in frontal cortex, thalamus and cerebellum were found in autistic boys, but not in autistic girls nor in the majority of siblings studied. We propose that abnormal serotonin synthesis plays a role in the pathophysiology of autism. In order to further characterize whole brain and focal abnormalities of serotonin synthesis in autistic children, we propose to use alpha[C-11]-Methyl-L-tryptophan imaged with PET to: 1. Determine whether autistic children differ from their siblings with expanded phenotype of autistic disorder, their normal siblings and epileptic children with regard to changes in values for whole brain serotonin synthesis capacity with age. 2. Determine whether there are abnormalities of serotonin synthesis in specific brain regions in autistic children. An understanding of the neurochemical disturbances in autism is important for the development of new treatment approaches.

自闭症是一种毁灭性的神经发育障碍，其特征是一系列异常行为，包括社交互动和沟通的严重障碍、行为、兴趣和活动的限制性重复和刻板模式，以及刻板运动异常。 调查自闭症患者血液中神经递质变化的研究一致发现，大约三分之一到二分之一的自闭症患者的血小板血清素增加。 然而，对脑脊液中血清素代谢物 5-HIAA 的研究未能证明中枢血清素能张力的一致异常。此前，还没有直接体内测量人体血清素合成的方法，只能进行间接且相对不敏感的测量。 Alpha[C-11]-甲基-L-色氨酸已被开发为正电子发射断层扫描 (PET) 血清素合成的示踪剂，现在可以直接体内测量人体血清素合成。利用这项技术，我们获得了初步数据，证明自闭症儿童的全脑血清素合成与其 8-14 岁的兄弟姐妹或 2-12 岁的癫痫儿童相比发生了变化。此外，我们还发现自闭症男孩和他们的兄弟姐妹之间的焦点差异。 在自闭症男孩中发现额叶皮层、丘脑和小脑的血清素合成不对称，但在自闭症女孩和大多数研究的兄弟姐妹中都没有发现。 我们认为血清素合成异常在自闭症的病理生理学中发挥着作用。 为了进一步表征自闭症儿童的全脑和局灶性血清素合成异常，我们建议使用 PET 成像的 α[C-11]-甲基-L-色氨酸来： 1. 确定自闭症儿童的全脑血清素合成能力值随年龄变化是否与自闭症扩展表型的兄弟姐妹、正常兄弟姐妹和癫痫儿童不同。 2.确定自闭症儿童特定脑区是否存在血清素合成异常。 了解自闭症的神经化学紊乱对于开发新的治疗方法非常重要。