IMAGING TRYPTOPHAN METABOLISM IN TUBEROUS SCLEROSIS

硬化症是一种常染色体显性遗传病， 疾病，现在已知是由至少两种不同的基因突变引起的。 基因，TSC 1和TSC 2。 这些遗传缺陷导致肿瘤生长 包括大脑皮肤心脏和肾脏 虽然脑损伤的神经后果是多种多样的， 两个主要问题是癫痫（影响80%以上的TSC 自闭症（影响17- 61%的TSC患者）。 的 该建议的中心假设是， 通过多巴胺能和/或犬尿氨酸途径的代谢有助于 TSC患儿癫痫和自闭症的病理生理学。 脑色氨酸代谢将在患有以下疾病的儿童体内进行测量： TSC使用示踪剂α [C-11]甲基-L-色氨酸（[C-11]AMT）， 正电子发射断层扫描（PET）。此外， 将在脑组织中测量血清素和犬尿氨酸途径 切除以控制顽固性癫痫。 在TSC患者中， 癫痫，我们使用[C-11]AMT PET的初步数据表明， 致痫区域[C-11]AMT摄取的局灶性增加 结节，但不与头皮相关的非致癫痫结节 脑电图（EEG）。 我们建议确认和延长这些 本提案中的调查结果。 在非TSC自闭症患者中，两者都 已经报道了5-羟色胺合成的局部和整体改变 我们的团队使用[C-11]AMT PET。 我们建议测试焦点是否 和全球血清素合成异常测量以前在非- TSC自闭症儿童也发现在自闭症儿童与TSC和 癫痫 本提案将涉及四个具体目标：（1） 确定是否存在[C-11]AMT蓄积增加 在TSC患儿的皮质结节内和周围， 致癫痫性(2)以确定潜在的生化机制 对于观察到的[C-11]AMT摄取增加， TSC患儿的块茎亚群。(3)为了确定自闭症患者 患有TSC和癫痫的儿童与非自闭症儿童不同， TSC和癫痫与全脑5-羟色胺变化的关系 合成能力随年龄增长而增强。(4)为了确定自闭症儿童 与患有TSC和癫痫的非自闭症儿童不同， 癫痫与丘脑局灶性[C-11]AMT异常有关， 小脑

Tuberous sclerosis complex (TSC) is an autosomal dominant inherited disorder, now known to result from mutations in at least two different genes, TSC1 and TSC2. These genetic defects result in tumorous growths in multiple organs, including the brain, skin, heart, and kidney. Although the neurological consequences of the brain lesions are diverse, two major problems are epilepsy (affecting more than 80 percent of TSC patients) and autism (affecting 17-61 percent of TSC patients). The central hypothesis of this proposal is that abnormalities tryptophan metabolism via the serotonergic and/or kynurenine pathways contribute to the pathophysiology of both epilepsy and autism in children with TSC. Brain tryptophan metabolism will be measured in vivo in children with TSC using the tracer alpha[C-11]methyl-L-tryptophan ([C-11]AMT) with positron emission tomography (PET). In addition, metabolites of the serotonin and kynurenine pathways will be measured in brain tissue resected for the control of intractable epilepsy. In TSC patients with epilepsy, our preliminary data using [C-11]AMT PET have demonstrated focal increases in [C-11]AMT uptake in the region of epileptogenic tubers, but not in nonepileptogenic tubers as correlated with scalp electroencephalogram (EEG). We propose to confirm and extend these findings in the present proposal. In non-TSC patients with autism, both focal and global alterations in serotonin synthesis have been reported by our group using [C-11]AMT PET. We propose to test whether the focal and global serotonin synthesis abnormalities measured previously in non- TSC autistic children are also found in autistic children with TSC and epilepsy. Four specific aims are to be addressed in this proposal: (1) To determine whether the presence of increased [C-11]AMT accumulation in and around cortical tubers in children with TSC indicate epileptogenicity. (2) To determine the underlying biochemical mechanism for the observed increase in [C-11]AMT uptake measured with PET in a subset of tubers in children with TSC. (3) To determine whether autistic children with TSC and epilepsy differ from non-autistic children with TSC and epilepsy with respect to changes in global brain serotonin synthesis capacity with age. (4) To determine whether autistic children with TSC and epilepsy differ from non-autistic children with TSC and epilepsy with regard to focal [C-11]AMT abnormalities in thalamus and cerebellum.