IMAGING TRYPTOPHAN METABOLISM IN TUBEROUS SCLEROSIS

结节性硬化症是一种常染色体显性遗传性疾病 疾病，现在已知由至少两个不同的基因突变引起 基因，TSC1和TSC2。这些遗传缺陷会导致肿瘤生长。 在多个器官中，包括大脑、皮肤、心脏和肾脏。 尽管脑部损伤的神经学后果各不相同， 两个主要问题是癫痫(影响80%以上的TSC 患者)和自闭症(影响17-61%的TSC患者)。这个 这一提议的中心假设是色氨酸的异常 5-羟色胺能和/或犬尿氨酸途径参与代谢 对癫痫和自闭症儿童的病理生理学的影响。 脑色氨酸代谢将在活体测量的儿童 示踪剂α[C-11]甲基L色氨酸([C-11]AMT)的薄层扫描 正电子发射断层扫描(PET)。此外，人体的代谢物 5-羟色胺和犬尿氨酸通路将在脑组织中进行测量 为控制顽固性癫痫而切除。在患有TSC的患者中 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，但不是与头皮相关的非致痫结节 脑电(EEG)。我们建议确认并延长这些条款 本提案中的调查结果。在患有自闭症的非TSC患者中，两者 5-羟色胺合成的局灶性和全局性改变已有报道 由我们小组使用[C-11]AMT PET。我们建议测试焦点是否 和以前测量的非 自闭症儿童也可在患有自闭症的儿童中发现。 癫痫。这项建议将涉及四个具体目标：(1) 以确定是否存在增加的[C-11]AMT累积 患有TSC的儿童皮质结节内和周围提示 致癫性。(2)确定潜在的生化机制 对于观察到的用PET测量的[C-11]AMT摄取的增加， TSC患儿的结节亚群。(3)确定自闭症患者是否 患有TSC和癫痫的儿童不同于非自闭症儿童 TSC与癫痫与全脑5-羟色胺的变化 综合能力随年龄增长。(4)确定自闭症儿童是否 TSC和癫痫不同于患有TSC和癫痫的非自闭症儿童 丘脑和丘脑局灶性[C-11]AMT异常与癫痫 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.