BRAIN SEROTONIN SYNTHESIS IN AUTISM

自闭症患者的大脑血清素合成

• 批准号: 6125577
• 负责人: DIANE C CHUGANI
• 金额: $ 24.45万
• 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/6125577
• 关键词: autism; bioimaging /biomedical imaging; 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.

自闭症是一种破坏性的神经发育障碍，其特征在于一系列异常行为，包括社会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，以及刻板的运动异常。 研究孤独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孤独症患者血小板血清素增加。 然而，对脑脊液中5-羟色胺代谢物5-HIAA的研究未能证明中枢多巴胺能紧张性的一致异常。以前，没有直接在体内测量人体5-羟色胺合成的方法，只能进行间接和相对不敏感的测量。 α [C-11]-甲基-L-色氨酸已被开发为正电子发射断层扫描（PET）5-羟色胺合成的示踪剂，现在可以直接在人体内测量5-羟色胺合成。使用这种技术，我们有初步的数据表明，与8-14岁的兄弟姐妹或2-12岁的癫痫儿童相比，自闭症儿童的全脑5-羟色胺合成发生了变化。此外，我们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了额叶皮层、丘脑和小脑中5-羟色胺合成的不对称性，但在自闭症女孩中没有发现，在大多数研究的兄弟姐妹中也没有发现。 我们认为异常的血清素合成在自闭症的病理生理学中起着重要作用。 为了进一步表征自闭症儿童全脑和局部5-羟色胺合成异常，我们建议使用PET成像的α [C-11]-甲基-L-色氨酸：1。确定自闭症儿童是否不同于他们的兄弟姐妹与扩展表型的自闭症，他们的正常兄弟姐妹和癫痫儿童的全脑5-羟色胺合成能力的值随年龄的变化。 2.确定自闭症儿童特定脑区是否存在5-羟色胺合成异常。 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。