IMAGING TRYPTOPHAN METABOLISM IN TUBEROUS SCLEROSIS

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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.