AMT Uptake Research Articles

Abnormal brain tryptophan metabolism and clinical correlates in Tourette syndrome

Symptoms in Tourette syndrome (TS) are likely related to abnormalities involving multiple neurotransmitter systems in striatal-thalamo-cortical circuitry. Although prior studies have found abnormal levels of tryptophan, serotonin, and their metabolites in blood, cerebrospinal fluid and brain tissue of TS patients, understanding of focal brain disturbances and their relationship to clinical phenotype remains poor. We used alpha-[(11)C]methyl-L-tryptophan (AMT) positron emission tomography (PET) to assess global and focal brain abnormalities of tryptophan metabolism and their relationship to behavioral phenotype in 26 children with TS and nine controls. Group comparisons on regional cortical and subcortical AMT uptake revealed decreased AMT uptake in bilateral dorsolateral prefrontal cortical and bilaterally increased uptake in the thalamus (P = 0.001) in TS children. The ratio of AMT uptake in subcortical structures to dorsolateral prefrontal cortex was significantly increased bilaterally (P < 0.01) in TS patients also. Behaviorally defined subgroups within the TS sample revealed differences in the pattern of AMT uptake in the fronto-striatal-thalamic circuit. This study demonstrates cortical and subcortical abnormalities of tryptophan metabolism in TS and provides neuroimaging evidence for a role of serotonergic mechanisms in the pathophysiology of TS.

Assessment of Progression and Treatment Response of Optic Pathway Glioma with Positron Emission Tomography using α-[11C]Methyl-l-Tryptophan

To report the utility of positron emission tomography (PET) with alpha-[(11)C]methyl-L-tryptophan (AMT) for monitoring progression and response to treatment of an isolated optic pathway glioma (OPG) in a 16-year-old girl. Positron emission tomography scanning of the brain was performed 20 minutes after intravenous administration of AMT. The AMT-PET images were reconstructed and examined for tumor uptake of the tracer in correlation with coregistered magnetic resonance images. The PET scan demonstrated increased uptake of AMT by OPG in a clinically symptomatic child whose magnetic resonance imaging (MRI) was inconclusive for morphological changes of the tumor. The tracer uptake was dramatically decreased on the images obtained after chemotherapy. Subsequently, AMT-PET revealed a new tumor lesion of increased AMT uptake when the patient developed vision problems and MRI showed no significant interval morphological changes. Significant vision improvement was observed after external beam radiotherapy for the newly identified tumor lesion. Positron emission tomography with alpha-[(11)C]methyl-L-tryptophan may be useful for monitoring progression and response to treatment of OPGs, which needs to be further investigated in a prospective study of more patients, including those with neurofibromatosis.

Cerebellar Lesions in Tuberous Sclerosis Complex

We assessed the structural and functional imaging features of cerebellar lesions and their neurobehavioral correlates in a large cohort of patients with tuberous sclerosis complex. A consecutive series of 78 patients with tuberous sclerosis complex underwent magnetic resonance imaging (MRI) and positron emission tomography (PET) studies with [(18)F]fluorodeoxyglucose (FDG) and alpha-[(11)C]methyl-l-tryptophan (AMT) as part of their evaluation for epilepsy surgery. Neurobehavioral assessment included the Gilliam Autism Rating Scales (GARS) and the Vineland Adaptive Behavior Scales (VABS). Twenty-one patients (27%) had cerebellar lesions (10 boys; mean age 9 +/- 8 years; 9 had right-sided, 10 had left-sided, and 2 had bilateral cerebellar lesions). The lesions showed decreased glucose metabolism (0.79 +/- 0.10) and increased (1.04 +/- 0.10) AMT uptake compared with the normal (nonlesional) cerebellar cortex. Comparisons between patients with (n = 20) and without (n = 57) a cerebellar lesion on neurobehavioral functioning, controlling for the number and location of cortical tubers, revealed that the cerebellar lesion group had higher overall autistic symptomatology. Within-group analyses of the cerebellar lesion group revealed that children with right-sided cerebellar lesions had higher social isolation and communicative and developmental disturbance compared with children with left-sided cerebellar lesions. The side of the cerebellar lesion was not related to adaptive behavior functioning. These findings provide additional empiric support for a role of the cerebellum in autistic symptomatology. Further investigation of the potential role of the right cerebellum in autism, particularly with regard to the dentatothalamofrontal circuit, is warranted.

EPILEPSY SURGERY FOR NEONATAL OR INFANTILE ONSET SEIZURES: USE OF PET SCANNING

Intractable epilepsy in infants and young children may lead to an epileptic encephalopathy. In such cases, epilepsy surgery should be considered. Surgical results are best when there is concordance between EEG localization and neuroimaging. PET scanning using 2-deoxy-2(18F)fluoro-D-glucose (FDG) identifies epileptic foci when MRI is non-revealing, and when a lesion is present, PET complements MRI by defining the full extent of the lesion and evaluating the integrity of surrounding brain regions. PET abnormalities may guide placement of intracranial electrodes, thus minimizing sampling errors. The size of the hypometabolic zone increases with chronic epilepsy, suggesting dynamic changes in the epileptic network. In infantile spasms, resection of focal PET abnormalities corresponding to focal EEG abnormalities is associated with improved seizure/cognitive outcome. Only about 20% of patients with 'cryptogenic infantile spasms' show a single PET focus amenable to resection. The majority shows multifocal hypometabolism and are not optimal surgical candidates. Bilateral symmetric hypometabolism suggests a nonlesional etiology, more consistent with neurogenetic/neurometabolic disorders. In infants with hemimegalencephaly, the relative integrity of the contralateral hemisphere is assessed using PET for prognostic purposes. In patients with Sturge-Weber syndrome, rapid demise of the affected hemisphere is associated with better seizure/cognitive outcome than slower progression because of brain plasticity. Other PET tracers may provide more specific assessment of seizure foci. 11C-flumazenil (FMZ) labels central benzodiazepine receptors, showing: decreased receptor binding in medial temporal sclerosis, perilesional epileptogenic zones, seizure onset zones, and secondary epileptic foci. 11C-alpha-methyl-L-tryptophan (AMT), an analogue of tryptophan, traces serotonin synthesis and kynurenine pathways and shows increased uptake in epileptogenic cortex interictally. In children with tuberous sclerosis, increased AMT uptake is seen around epileptogenic tubers, but not nonepileptogenic tubers. The list of PET tracers for epilepsy continues to grow and will eventually pinpoint precisely the cortical regions that should be resected to achieve best postoperative outcome.

In VivoUptake and Metabolism of α-[11C]Methyl-l-Tryptophan in Human Brain Tumors

Abnormal metabolism of tryptophan has been implicated in modulation of tumor cell proliferation and immunoresistance. alpha-[(11)C]Methyl-L-tryptophan (AMT) is a PET tracer to measure cerebral tryptophan metabolism in vivo. In the present study, we have measured tumor tryptophan uptake in 40 patients with primary brain tumors using AMT PET and standard uptake values (SUV). Tryptophan metabolism was further quantified in 23 patients using blood input data. Estimates of the volume of distribution (VD') and the metabolic rate constant (k(3)') were calculated and related to magnetic resonance imaging (MRI) and histology findings. All grade II to IV gliomas and glioneuronal tumors showed increased AMT SUV, including all recurrent/residual tumors. Gadolinium enhancement on MRI was associated with high VD' values, suggesting impaired blood-brain barrier, while k(3)' values were not related to contrast enhancement. Low-grade astrocytic gliomas showed increased tryptophan metabolism, as measured by k(3)'. In contrast, oligodendrogliomas showed high VD' values but lower k(3)' as compared with normal cortex. In astrocytic tumors, low grade was associated with high k(3)' and lower VD', while high-grade tumors showed the reverse pattern. The findings show high AMT uptake in primary and residual/recurrent gliomas and glioneuronal tumors. Increased AMT uptake can be due to increased metabolism of tryptophan and/or high volume of distribution, depending on tumor type and grade. High tryptophan metabolic rates in low-grade tumors may indicate activation of the kynurenine pathway, a mechanism regulating tumor cell growth. AMT PET might be a useful molecular imaging method to guide therapeutic approaches aimed at controlling tumor cell proliferation by acting on tryptophan metabolism.

Epilepsy Surgery Outcome in Children With Tuberous Sclerosis Complex Evaluated With α-[11C]Methyl-L-Tryptophan Positron Emission Tomography (PET)

Tuberous sclerosis complex is commonly associated with medically intractable seizures. We previously demonstrated that high uptake of alpha-[11C]methyl-L-tryptophan (AMT) on positron emission tomography (PET) occurs in a subset of epileptogenic tubers consistent with the location of seizure focus. In the present study, we analyzed the surgical outcome of children with tuberous sclerosis complex in relation to AMT PET results. Seventeen children (mean age 4.7 years) underwent epilepsy surgery, guided by long-term videoelectroencephalography (EEG) (including intracranial EEG in 14 cases), magnetic resonance imaging (MRI), and AMT PET. AMT uptake values of cortical tubers were measured using regions of interest delineated on coregistered MRI and were divided by the value for normal-appearing cortex to obtain an AMT uptake ratio. Based on surgical outcome data, tubers showing increased AMT uptake (uptake ratio greater than 1.00) were classified into three categories: (1) epileptogenic (tubers within an EEG-defined epileptic focus whose resection resulted in seizure-free outcome), (2) nonepileptogenic (tubers that were not resected but the patient became seizure free), or (3) uncertain (all other tubers). Increased AMT uptake was found in 30 tubers of 16 children, and 23 of these tubers (77%) were located in an EEG-defined epileptic focus. The tuber with the highest uptake was located in an ictal EEG onset region in each patient. Increased AMT uptake indicated an epileptic region not suspected by scalp EEG in four cases. Twelve children (71%) achieved seizure-free outcome (median follow-up 15 months). Based on outcome criteria, 19 of 30 tubers (63%) with increased AMT uptake were epileptogenic, and these tubers had significantly higher AMT uptake than the nonepileptogenic ones (P = .009). Tubers with at least 10% increase of AMT uptake (in nine patients) were all epileptogenic. Using a cutoff threshold of 1.02 for AMT uptake ratio provided an optimal accuracy of 83% for detecting tubers that needed to be resected to achieve a seizure-free outcome. The findings suggest that resection of tubers with increased AMT uptake is highly desirable to achieve seizure-free surgical outcome in children with tuberous sclerosis complex and intractable epilepsy. AMT PET can provide independent complementary information regarding the localization of epileptogenic regions in tuberous sclerosis complex and enhance the confidence of patient selection for successful epilepsy surgery.

Evaluation with alpha-[11C]methyl-L-tryptophan positron emission tomography for reoperation after failed epilepsy surgery.

Reoperation after failed cortical resection can alleviate seizures in patients with intractable neocortical epilepsy, provided that previously nonresected epileptic regions are accurately defined and removed. Most imaging modalities have limited value in identifying such regions after a previous surgery. Positron emission tomography (PET) using alpha-[11C]methyl-L-tryptophan (AMT) can detect epileptogenic cortical areas as regions with increased tracer uptake. This study analyzed whether increased cortical AMT uptake can detect nonresected epileptic foci in patients with previously failed neocortical resection. Thirty-three young patients (age 3-26 years; mean age, 10.8 years) with intractable epilepsy of neocortical origin, and a previously failed cortical resection performed at various epilepsy centers, underwent further presurgical evaluation for reoperation. AMT-PET scans were performed 6 days to 7 years after the first surgery. Focal cortical areas with increased AMT uptake were objectively identified and correlated to ictal EEG data as well as clinical variables (age, postsurgical time, etiology). Cortical increases of AMT uptake were detected on the side of the previous resections in 12 cases. In two patients scanned shortly (within a week) after surgery, diffuse hemispheric increases were observed, without any further localization value. In contrast, in 10 (43%) of 23 patients scanned >2 months but within 2.3 years after surgery, focal cortical increases occurred, concordant with seizure onset on ictal EEG. Age, etiology (lesional vs. cryptogenic), epileptiform EEG activity during PET, or time of the last seizure were not significantly related to the presence of increased AMT uptake. All patients with localizing AMT-PET, who underwent reoperation, became seizure free (n = 5) or showed considerable improvement of seizure frequency (n = 2). AMT-PET can identify nonresected epileptic cortex in patients with a previously failed neocortical epilepsy surgery and, with proper timing for the scan, can assist in planning reoperation.

Autism in tuberous sclerosis complex is related to both cortical and subcortical dysfunction.

To examine the relationship between autism and epilepsy in relation to structural and functional brain abnormalities in children with tuberous sclerosis complex (TSC). Children with TSC and intractable epilepsy underwent MRI as well as PET scans with 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) and alpha-[(11)C]methyl-L-tryptophan (AMT). Based on the results of Autism Diagnostic Interview-Revised, Gilliam Autism Rating Scale, and overall adaptive behavioral composite (OABC) from Vineland Adaptive Behavior Scale, subjects were divided into three groups: autistic (OABC < 70; n = 9), mentally-retarded nonautistic (OABC < 70; n = 9), and relatively normal intelligence (OABC > or = 70; n = 8). PET studies showed that the autistic group had decreased glucose metabolism in the lateral temporal gyri bilaterally, increased glucose metabolism in the deep cerebellar nuclei bilaterally, and increased AMT uptake in the caudate nuclei bilaterally, compared to the mentally-retarded nonautistic group. In addition, a history of infantile spasms and glucose hypometabolism in the lateral temporal gyri were both significantly associated with communication disturbance. Glucose hypermetabolism in the deep cerebellar nuclei and increased AMT uptake in the caudate nuclei were both related to stereotypical behaviors and impaired social interaction, as well as communication disturbance. These results suggest that generalized epilepsy in early life and functional deficits in the temporal neocortices may be associated with communication delays, and that functional imbalance in subcortical circuits may be associated with stereotypical behaviors and impaired social interaction in children with TSC.

Multimodality imaging for improved detection of epileptogenic foci in tuberous sclerosis complex.

Using interictal alpha-[11C]methyl-l-tryptophan ([11C]AMT) PET scan, the authors have undertaken a quantitative analysis of all tubers visible on MRI or 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) PET, to determine the relationship between [11C]AMT uptake and epileptic activity on EEG. Tuberous sclerosis complex (TSC) is an autosomal dominant disorder, often associated with cortical tubers and intractable epilepsy. The authors have shown previously that [11C]AMT PET scans show high tracer uptake in some epileptogenic tubers and low uptake in the remaining tubers. Eighteen children, age 7 months to 16 years, were studied. Patients underwent video-EEG monitoring, PET scans of [11C]AMT and [18F]FDG, and T2-weighted or fluid-attenuated inversion recovery (FLAIR) MRI. [11C]AMT uptake values were measured in 258 cortical tubers delineated with coregistered MRI or [18F]FDG scans. Uptake ratios were calculated between the [11C]AMT uptake in tubers and those for normal cortex (tuber/normal cortex). Using the region of epileptiform activity, the authors performed receiver operator characteristics (ROC) analysis and determined the optimal uptake ratio for detecting presumed epileptogenic tubers. Tuber uptake ratios ranged from 0.6 to 2.0. Tuber uptake ratios in the epileptic lobes were higher than those in the nonepileptic lobes (p < 0.0001). All 15 patients with focal seizure activity showed one or more lesions with uptake ratio above 0.98 in the epileptic lobe. ROC analysis showed that a tuber uptake ratio of 0.98 resulted in a specificity of 0.91. Cortical tubers with [11C]AMT uptake greater than or equal to normal cortex are significantly related to epileptiform activity in that lobe. Together, interictal [11C]AMT PET and FLAIR MRI improve the detection of potentially epileptogenic tubers in patients with TSC being evaluated for epilepsy surgery.

Imaging epileptogenic tubers in children with tuberous sclerosis complex using alpha-[11C]methyl-L-tryptophan positron emission tomography.

Several reports have indicated that cortical resection is effective in alleviating intractable epilepsy in children with tuberous sclerosis complex (TSC). Because of the multitude of cortical lesions, however, identifying the epileptogenic tuber(s) is difficult and often requires invasive intracranial electroencephalographic (EEG) monitoring. As increased concentrations of serotonin and serotonin-immunoreactive processes have been reported in resected human epileptic cortex, we used alpha-[11C]methyl-L-tryptophan ([11C]AMT) positron emission tomography (PET) to test the hypothesis that serotonin synthesis is increased interictally in epileptogenic tubers in patients with TSC. Nine children with TSC and epilepsy, aged 1 to 9 years (mean, 4 years 1 month), were studied. All children underwent scalp video-EEG monitoring, PET scans of glucose metabolism and serotonin synthesis, and EEG monitoring during both PET studies. [11C]AMT scans were coregistered with magnetic resonance imaging and with glucose metabolism scans. Whereas glucose metabolism PET showed multifocal cortical hypometabolism corresponding to the locations of tubers in all 9 children, [11C]AMT uptake was increased in one tuber (n=3), two tubers (n=3), three tubers (n=1), and four tubers (n=1) in 8 of the 9 children. All other tubers showed decreased [11C]AMT uptake. Ictal EEG data available in 8 children showed seizure onset corresponding to foci of increased [11C]AMT uptake in 4 children (including 2 with intracranial EEG recordings). In 2 children, ictal EEG was nonlocalizing, and in 1 child there was discordance between the region of increased [11C]AMT uptake and the region of ictal onset on EEG. The only child whose [11C]AMT scan showed no regions of increased uptake had a left frontal seizure focus on EEG; however, at the time of his [11C]AMT PET scan, his seizures had come under control. [11C]AMT PET may be a powerful tool in differentiating between epileptogenic and nonepileptogenic tubers in patients with TSC.

Retention of indoles in the pineal organ of the bird (Melopsittacus undulatus, Shaw) during its preparation for radioautographic study

Since high-resolution radioautography (dipping technique) might be very useful for the study of indole metabolism in the pineal cells, the retention of [3H]-indoles has to be examined during the preparation of specimens for electron microscopy (EM). The pineal organ of the parakeet (Melopsittacus undulatus) was used in the present work. 1) Indole metabolism: following uptake of [3H]-5-hydroxytryptophan ([3H]-HW) in vivo and [3H]-5-hydroxytryptamine ([3H]-HT) in vitro in similar seasonal and nycthemeral conditions--all the known pineal indolic metabolites were recovered by thin layer chromatography. [3H]-5-methoxyindoles were also formed from [3H]-melatonin ([3H]-aMT). 2) The radioactivity of fluids used in the processing of pineal organs in EM was determined by liquid scintillation counting: (a) no exogenous [3H]-indoles could be revealed in EM solutions after [3H]-HW in vivo uptake. (b) 8.8 to 13.4% of [3H]-indoles were washed out by glutaraldehyde after [3H]-HT in vitro uptake. (c) most of the 5-methoxyindoles after in vitro uptake of [3H]-aMT were lost in glutaraldehyde. Our chromatography procedures did not permit the identification of [3H]-indoles extracted by the glutaraldehyde fixative. In previous experiments, [3H]-HW and [3H]-HT uptake showed the presence of selective radioautographic reactions in the cells of the receptor line; however, silver grains were scarce and diffusely distributed in the pineal parenchyma after [3H]-aMT uptake.