BRAIN SEROTONIN SYNTHESIS IN AUTISM

自闭症是一种破坏性的神经发育障碍，其特征是一系列异常行为，包括严重的社交和沟通障碍，限制性重复和刻板印象的行为、兴趣和活动模式，以及刻板印象的运动异常。调查自闭症患者血液中神经递质变化的研究一直发现，大约三分之一至一半的自闭症患者的血小板5-羟色胺升高。然而，对脑脊液中5-羟色胺代谢产物5-HIAA的研究未能证明中枢5-羟色胺能张力的一致异常。以前，还没有直接测量人体内5-羟色胺合成的方法，只能进行间接的和相对不敏感的测量。α[C-11]-甲基-L-色氨酸已被开发为5-羟色胺合成的正电子发射断层扫描示踪剂，现在可以直接在体内测量人类5-羟色胺的合成。使用这项技术，我们有初步数据显示，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，我们还发现了自闭症男孩和他们的兄弟姐妹之间的局部差异。在自闭症男孩的额叶皮质、丘脑和小脑中发现了5-羟色胺合成的不对称性，但在自闭症女孩和大多数研究的兄弟姐妹中没有发现。我们认为5-羟色胺合成异常在自闭症的病理生理学中起作用。为了进一步确定自闭症儿童全脑和局灶性5-羟色胺合成异常的特征，我们建议使用α[C-11]-甲基-L-色氨酸正电子发射计算机断层扫描来：1.确定自闭症儿童与自闭症表型扩大的兄弟姐妹、正常兄弟姐妹和癫痫儿童的全脑5-羟色胺合成能力值随年龄的变化是否不同。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障碍对于开发新的治疗方法很重要。

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.