The present study compared the availability of the 5-HT2A receptor in the brains of adults with Asperger’s Disorder and matched healthy controls. 5-HT2A receptor availability was numerically, but not statistically, greater in the Asperger’s Disorder group in every ROI. In addition, there were no significant differences in availability of the SERT in a subset of patients when compared to healthy controls, although individuals with Asperger’s Disorder had numerically decreased SERT availability in every ROI.
This study failed to demonstrate significant differences in 5-HT2A receptor availability in patients with Asperger’s Disorder and matched healthy controls. Based on results of treatment, imaging, biochemical, and challenge studies that suggest deficiencies of central nervous system serotonin in ASD, the study hypothesis was that 5-HT2A receptor availability might be increased in patients with Asperger’s Disorder, reflecting a compensatory upregulation of these receptors. While the group average of [11C]MDL 100907 BPND was indeed found to be numerically increased in patients in every ROI, this increase failed to reach statistical significance. Since the regional data were suggestive of a global effect, we performed a mixed model analysis to explore the possibility that the difference in 5-HT2A receptor availability was global. However, group differences in this analysis were also non-significant.
These results are discrepant with one previous SPECT study of the 5-HT2A
receptor in ASD (Murphy et al., 2006
). In the previous study, Murphy et al. used the radiotracer [123
I]-5-I-R91150 with eight adults with Asperger’s Disorder and found decreased 5-HT2A
receptor availability in patients compared to 10 healthy controls in anterior and posterior cingulate, frontal and superior temporal cortex bilaterally, and in the left parietal cortex (Murphy et al., 2006
). Differences between the previous study and the current results may be the result of differences in sample size, as well as the use of SPECT versus PET. PET generally has greater spatial resolution than SPECT, is more sensitive, and provides for more accurate attenuation correction. An additional strength of our study is the use of arterial input with full kinetic analysis. The contribution of each of these differences to the discordant findings is unclear.
The primary limitation of our study of the 5-HT2A receptor is that we used adults with Asperger’s Disorder with normal intellectual functioning, as opposed to children, individuals with other ASDs (e.g., autistic disorder), or individuals with ASD and cognitive delays. It would be interesting to investigate the 5-HT2A receptor in these other groups of individuals with PDD. However, ethical concerns preclude the administration of radioactivity to children and adolescents (i.e., due to their age), and to individuals who are more severely affected with psychiatric illness (i.e., due to capacity considerations). Therefore, the findings from this study may not be generalizable to the full spectrum of PDDs.
We also investigated the availability of the SERT in a subset of patients and compared them with matched controls. We found group averages of BPND were lower in the Asperger’s group than controls in every region, but none of these were statistically significant. It is possible that the [11C]DASB sample size (N=8) was too small to detect smaller differences in SERT availability between individuals with Asperger’s Disorder and healthy control subjects. A larger sample would provide more power to detect possible group differences. Therefore, these results should be considered preliminary and replication studies are warranted.
Previous imaging studies reported decreased SERT levels in ASD. In particular, Nakamura et al. studied 20 adults with high-functioning autism and 20 matched healthy control subjects and used [11
C] (+)McN-5652 to label the SERT (Nakamura et al., 2010
). They found global decreases in the availability of the SERT in patients (Nakamura et al., 2010
), as well as correlations between reductions in SERT in anterior and posterior cingulate and measures of social cognition and between reductions in SERT in thalamus and severity of repetitive/obsessive compulsive behaviors. However, the study of Nakamura et al. (Nakamura et al., 2010
) reported distribution volumes, rather than binding potentials. Distribution volume measures both specific and non-specific binding and is dependent on the input to the compartment of interest, among other components (Innis et al., 2007
). Furthermore, Nakamura et al. (Nakamura et al., 2010
) demonstrated differences in cerebellar distribution volumes, a region in which there is essentially no specific binding with [11
C] (+)McN-5652, as well as differences in distribution volumes in cortical regions, areas in which the signal from [11
C] (+)McN-5652 binding is too low to be accurately measured (Parsey et al., 2000
). This suggests that the distribution volumes reported by Nakamura et al. (Nakamura et al., 2010
) may have included effects due to non-specific SERT binding. Other notable differences between the study of Nakamura et al. (Nakamura et al., 2010
) and ours are the samples sizes, diagnoses of autism versus Asperger’s Disorder, and choice of radiotracer. One major difference between [11
C]DASB and [11
C] (+)McN-5652 is that [11
C]DASB provides higher BPND
C] (+)McN-5652, which allows greater reliability in assessment of the SERT (Frankle et al., 2004
; Szabo et al., 2002
Makkonen et al. (Makkonen et al., 2008
) used SPECT and the radiotracer [123
I] nor-beta-CIT in 15 children and adolescents with autism and 10 non-autistic comparison subjects and found decreased SERT capacity in medial prefrontal cortex in patients compared to control subjects. However, [123
I] nor-beta-CIT is limited as a measure of SERT to the midbrain given its nonspecificity and the relatively low concentration of SERT in other regions, such as the cortex (Laruelle et al., 1993
; Neumeyer et al., 1991
). Therefore, findings in regions other than midbrain should be interpreted with caution. Other notable differences between the study of Makkonen et al. and the current study are the sample sizes, the use of SPECT versus PET, the diagnoses of autism versus Asperger’s Disorder, the ages of the participants, and that we used healthy controls for comparison while all of the control subjects in the study of Makkonen et al. had other neurological diagnoses (Makkonen et al., 2008
To our knowledge, there are no studies specifically looking at the validity and reliability of scanning with [11
C]MDL 100907 and [11
C]DASB on the same day. However, it is unlikely that scanning with these two ligands on the same day obscured group differences in this protocol for several reasons: 1) DASB is highly selective for the SERT (Ki
in rat cells of 1.1nM) compared to 5-HT2A
receptors (Wilson et al., 2000
); 2) MDL 100907 is highly selective for 5-HT2A
between 0.14nM and 1.86nM in human cells) compared to SERT (Ki
> 10,000nM) as per the NIMH’s Psychoactive Drug Screening Program (http://pdsp.med.unc.edu/
); thus, direct interaction between the tracers was highly unlikely; 3) Tracer doses (i.e., doses that lead to less than 5% occupancy) of MDL 100907 and DASB were used in this study. As MDL 100907 is an antagonist and DASB is a reuptake inhibitor, tracer doses are likely to have no pharmacologic effects; 4) Both the Asperger’s Disorder and healthy control groups participated in the same study design; and 5) The order of the injection was alternated, so that 50% of the subjects underwent the [11
C]DASB scan first, and 50% underwent the [11
C]MDL 100907 scan first.
In conclusion, this study found no significant differences in 5-HT2A receptor and SERT availabilities in patients with Asperger’s Disorder compared to controls and failed to replicate the results of previous imaging studies of serotonin biomarkers in this condition. Replication studies using [11C]MDL 100907 and [11C]DASB in individuals with Asperger’s Disorder are needed to confirm the results of this study.