Objective: The cause of autistic spectrum disorder (i.e., autism and Asperger’s syndrome) is unknown. The serotonergic (5-HT) system may be especially implicated. However, cortical 5-HT 2Areceptor density in adults with the disorder has not been examined, to the authors’ knowledge.Method: The authors investigated cortical 5-HT 2A receptor binding in eight adults with Asperger’s syndrome and in 10 healthy comparison subjects with single photon emission computed tomography and the selective 5-HT 2A receptor ligand 123I iodinated 4-amino-N-[1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]-5-iodo-2-methoxybenzamide ( 123 I-5-I-R91150). Results: People with Asperger’s syndrome had a significant reduction in cortical 5-HT 2A receptor binding in the total, anterior, and posterior cingulate; bilaterally in the frontal and superior temporal lobes; and in the left parietal lobe. Also, reduced receptor binding was significantly related to abnormal social communication. Conclusions: The authors’ findings suggest that adults with Asperger’s syndrome have abnormalities in cortical 5-HT 2A receptor density and that this deficit may underlie some clinical symptoms.
Autistic spectrum disorder (comprising the subtypes of autism, Asperger’s syndrome, and pervasive developmental disorder not otherwise specified) affects approximately 60 per 10,000 people and is characterized by pervasive abnormalities in socioemotional communication and stereotypical and obsessional behaviors.
The cause of autistic spectrum disorder is poorly understood and is most likely multifactorial; however, the serotonergic (5-HT) system may be especially implicated. In nonhuman primates and nonautistic humans, the 5-HT system modulates social behavior, amygdala response to facial emotion (1) , and repetitive behaviors (see reference 2 for a review). Furthermore, the 5-HT 2A receptor modulates personality traits, such as harm avoidance (3) . People with autistic spectrum disorder are reported to have a significant decrease in platelet 5-HT 2A receptor binding (4 , 5) , and the 5-HT 2A receptor gene is a functional candidate gene in autism (see reference 6 for a review).
Thus, people with autistic spectrum disorder may have abnormalities in 5-HT 2A receptors. However, no one has directly investigated in vivo brain 5-HT 2A receptor binding in non-mentally retarded adults, to our knowledge. Therefore, we measured cortical 5-HT 2A receptor binding in adults with Asperger’s syndrome and in comparison subjects with single photon emission computed tomography (SPECT) and the selective 5-HT 2A receptor ligand 123I iodinated 4-amino-N-[1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]-5-iodo-2-methoxybenzamide ( 123 I-5-I-R91150). Based on prior work (4 , 5) , we tested the hypothesis that in people with Asperger’s syndrome, cortical 5-HT 2A receptors are significantly decreased.
METHODS
We studied eight adult men with Asperger’s syndrome (full-scale IQ measured with the WAIS-III: >80, range=80–120; age: mean=26 years, SD=6) who were educated until they were at least 18 years and 10 healthy male comparison subjects who did not differ significantly in age or education. All volunteers were diagnosed with ICD-10 criteria and the Autistic Diagnostic Interview—Revised (7) . For people with Asperger’s syndrome, the mean scores on the Autistic Diagnostic Interview—Revised for domain A (qualitative abnormalities in reciprocal social interaction), domain B (qualitative abnormalities in communication), and domain C (repetitive behavior) were, respectively, mean=18 (SD=3), mean=13 (SD=6), and mean=6 (SD=3).
People were excluded if they had a history of physical or psychiatric disorder affecting brain function (e.g., epilepsy), a genetic disorder associated with autistic spectrum disorder (e.g., fragile X syndrome), or clinically abnormal magnetic resonance imaging. The study had ethical approval. No subject was taking any medication, and none reported past use of any psychotropic medication (e.g., selective serotonin reuptake inhibitors).
SPECT scans were performed at the Institute of Nuclear Medicine, Middlesex Hospital, University College London Medical School, with a three-headed PRISM 3000XP scanner (Phillips Medical Systems, Cleveland) with low-energy ultra-high-resolution fan-beam collimators. A bolus dose of 180 MBq of 123I-5-I-R91150 was administered intravenously. Sequential whole-brain images were acquired through a period of stable binding at pseudoequilibrium from 120 minutes to 280 minutes postinjection.
Whole-brain images were acquired with a resolution of 9–11 mm full width at half maximum. A transmission scan template, with a corresponding 123 I-5-I-R91150 specific emission scan template, was generated. As previously described, data were analyzed with the researcher automatically blind to subject status (e.g., see reference 8). In brief, cerebellar and cortical regions of interest based on the Talairach atlas were drawn on the emission scan template brain, and subsequent automatic data analysis examined between-group differences independent of the operator. The individual reconstructed and realigned image volumes were coregistered to the template images by using a nine-parameter (three-translation, three-rotation, and three-scaling) transformation based on the transmission image. Thus, mean activity per voxel for each region of interest was generated automatically for each subject. Average cerebellar uptake was used as a reference region because it is virtually devoid of 5-HT 2A receptors. Thus, an estimated binding potential can be generated for each cortical region by calculating the cortical/cerebellar ratio for each cortical region during the period of pseudoequilibrium.
Data were first examined for normality of distribution to conform to the assumptions of the statistics employed. Between-group differences in mean 5-HT 2A estimated binding potential were examined by using a nonparametric test (Mann-Whitney U, two-tailed), and statistical significance was defined as p<0.05. Also, within those with Asperger’s syndrome, we carried out a preliminary analysis (with a nonparametric test: Kendall’s tau) of the relationship between estimated binding potential and clinical symptoms as measured by the score on each of the three domains of the Autistic Diagnostic Interview—Revised. To reduce the number of statistical comparisons, we correlated only the estimated binding potential of the brain regions that were significantly different from those of the comparison subjects.
RESULTS
The individuals with Asperger’s syndrome had a significantly lower mean 5-HT 2A estimated binding potential than the comparison subjects in the anterior and posterior cingulate cortex, in the frontal and superior temporal cortex bilaterally, and in the left parietal cortex ( Table 1 ). Also, estimated binding potential in the anterior and posterior cingulate and the right frontal cortex was significantly correlated with increased qualitative abnormalities in reciprocal social interaction (domain A of the Autistic Diagnostic Interview—Revised); in each of these three regions, r=–0.837 and p<0.02.
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