New PET Technique Provides New Clues to Autism
abstract & commentary
Source: Chugani DC, et al. Developmental changes in brain serotonin synthesis capacity in autistic and non-autistic children. Ann Neurol 1999;45:287-295.
Autism, as noted in a recent Neurology Alert, remains a puzzling disorder continuing from infancy. Although some groups have reported small changes in brain structure (Plum F. Neurol Alert 1998;16:89-91), others have failed to detect functional changes using quantitative MRI (Piven J, et al. Neurology 1997; 49:546-551). Conventional neurological investigations fail to explain the profound symptoms in these children. Using a new PET technique that enables the study of brain serotonin synthesis capacity, Chugani and associates now report direct evidence for significant abnormalities in the development of serotonin synthesis capacity in autistic patients.
PET has evolved into a technique that can be used quantitatively to probe various neurochemical systems. The recent development of (11C)-alpha-methyl-tryptophan [(11C)-AMT] has enabled the study of serotonin (5-hydoxytryptamine) synthesis in humans (Nishizawa S, et al. PNAS 1997;94:5308-5313). (11C)-AMT uptake directly reflects serotonin synthesis capacity, i.e., it reflects the maximal rate at which serotonin could be synthesized if all tryptophan taken up were to be converted to serotonin. (11C)-AMT uptake is not a direct measure of serotonin synthesis rate, since there are multiple metabolic pools for tryptophan and other potential rate-limiting steps of serotonin synthesis (e.g., tryptophan hydroxylase).
Chugani et al examined whole brain serotonin synthesis capacity in 30 autistic patients, eight normal siblings of autistic patients, and 16 children with epilepsy. The youngest patient in the study was a 3-month-old epileptic infant, demonstrating applicability of the technique to young infants. Chugani et al found a decline in serotonin synthesis capacity among nonautistic children (control or epileptic) from age 2 to age 15, at which point synthesis capacity approaches adult values. As compared to either control group or epileptic patients, autistic patients: 1) show a significantly smaller increase (relative to normal adult values) in serotonin synthesis capacity during childhood and, 2) fail to show the age-related decreases in serotonin synthesis capacity seen in nonautistic children. In short, serotonin synthesis capacity seems to have lost most of its "developmental dynamism" in the autistic patient.
Commentary
The study by Chugani et al provides further evidence for abnormalities in serotonergic systems in autism, which Cook (Cook EH. Synapse 1990;6:292-308), had already suspected. The study suggests a defective developmental regulation of development and attrition of serotonergic mechanisms in autism. Indeed, the results concur with more recent findings by Cook et al (Cook EH, et al. Mol Psychiatry 1997;2:247-250), that certain poorly transcribed polymorphisms in a serotonin transporter frequently affect autistic families. The finding suggests a possible molecular basis for the differences seen in (11C)-AMT PET.
Differences in serotonin synthesis capacity between autistic and nonautistic children appear most marked during infancy. Hopefully, (11C)-AMT PET may identify that the defect exists in infancy in high-risk families before a clinical diagnosis is established (often not made until age 2). Unfortunately, it is not yet clearly established if the changes seen in autistic patients are entirely specific for that disorder. Serotonin reuptake inhibitors (SRIs) are already being given increasingly to both adults and children with autism (McDougle CJ, et al. Arch Gen Psychiatry 1996;53[11]:1001-1008 and 1998; 55:633-641; Fatemi SH, et al. J Autism Dev Disord 1998; [Aug 28]:303-307). Whether this improves the person’s development or adult life is unclear.
This was a cross-sectional study and "developmental changes" were inferred by examining serotonin synthesis capacity measurements among different patients of different ages. It would be valuable to follow a cohort of autistic patients over time in order to examine developmental differences in serotonin synthesis capacity in a given patient. Autism is a syndrome not yet identified as a specific disease. If, however, similar abnormalities in serotonin synthesis capacity were found in different autistic patients, heredity would be a likely common denominator of the disease.
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