Metabotropic Glutamate Receptor Subtype 5 in Males With Autism Spectrum Disorder: Preliminary Findings of a [11C]ABP688 Positron Emission Tomography Study

Mihov, Yoan Venceslavov; Akkus, Funda; Steinberg, Gerrit; Niemeyer, Jennifer; Hasler, Gregor (December 2017). Metabotropic Glutamate Receptor Subtype 5 in Males With Autism Spectrum Disorder: Preliminary Findings of a [11C]ABP688 Positron Emission Tomography Study. Neuropsychopharmacology, 43, S205-S206. Nature Publishing Group

Background: Preclinical investigations suggesting a therapeutic potential for metabotropic glutamate receptor subtype 5 (mGluR5) antagonists in fragile X syndrome raised interest in mGluR5 in neurodevelopment disorders in general, including autism spectrum disorder (ASD) (Davenport et al, 2016; Gogliotti and Conn, 2016; Scharf et al, 2015). To investigate the role of mGluR5 in ASD in vivo we carried out a positron emission tomography (PET) study with the mGluR5-selective radiotracer [11C]ABP688 in subjects with ASD and healthy controls.
Methods: Seventeen male subjects with ASD and 22 healthy male age-matched controls participated in this study. As our previous work showed that smoking profoundly and enduringly alters mGluR5 (Akkus et al, 2013), we matched both samples for smoking. As a result, the ASD sample included 11 non-smokers, 2 ex-smokers and four current smokers, and the control group 15 non-smokers, 2 exsmokers and five current smokers.
We assessed psychopathology in both study groups with the Structured Clinical Interview for DSM-IV Axis I (SCID-I), Beck Anxiety Inventory (BAI), and Beck Depression Inventory (BDI). In addition, we evaluated subjects with ASD using the Autism Diagnostic Observation Schedule (ADOS), Yale-Brown Obsessive Compulsive Scale (Y-BOCS), Obsessive Compulsive Inventory-Revised (OCI-R), Autism Quotient (AQ), and Empathy Quotient questionnaires (EQ).
We acquired PET data with a bolus/infusion protocol, as previously reported (Burger et al, 2010). In brief, [11C]ABP688 was administered in a 50- mL volume with an infusion pump. Our previous work shows that 40 min after the start of radioligand infusion equilibrium between [11C]ABP688 in tissue and blood is achieved. To calculate the relative distribution volume (DVR), we normalized the average of PET images acquired at 45-60 min after scan onset to the radioactivity concentration in the cerebellum. We used PMOD (PNEUROTool) and R for data analysis. We compared mGluR5 DVR in both groups in 33 brain regions using two-tailed Welch’s t-tests, without correction for multiple comparisons.
Results: Age did not differ significantly between subjects with ASD and controls when comparing the entire samples or their subgroups (all p-values>0.05, two-tailed). Overall, subjects with ASD scored higher in BAI and BDI (p<0.05, two-tailed).
We found no significant differences in mGluR5 DVR in any of the brain regions when comparing the entire samples comprising smokers, ex-smokers, and non-smokers (all p-values > 0.05, two-tailed). As expected, in both samples, smokers displayed globally decreased mGluR5 DVR (p<0.05, one-tailed). Due to the profound effect of smoking, we repeated our analyses in non-smokers only. This analysis revealed increased mGluR5 DVR in ASD in two regions: the straight gyrus and the posterior superior temporal gyrus (p<0.05, two-tailed). In addition, there was a trend for increased mGluR5 DVR in ASD in the postcentral gyrus (p<0.1, two-tailed). We did not find significantly decreased mGluR5 DVR in ASD in any brain region (p>0.05, two-tailed).
Exploratory correlation analyses involving BAI, BDI, AQ, EQ, and mGluR5 DVR in the straight gyrus, posterior superior temporal gyrus, and postcentral gyrus in nonsmokers with ASD yielded only one significant relationship: higher, i.e., more aberrant, mGluR5 DVR in the postcentral gyrus corresponded to lower, i.e., more aberrant, EQ score (Spearman’s rho = -0.64, p<0.05, two-tailed, uncorrected for multiple comparisons).
Conclusions: To our knowledge, this is the first in vivo investigation of mGluR5 in persons with ASD. Our findings suggest increased mGluR5 DVR in the straight gyrus, the posterior superior temporal gyrus, and the postcentral gyrus in male non-smokers with ASD. Due to the small sample size and the exploratory nature of the statistical analyses, these results remain preliminary. Nevertheless, our findings provide a preliminary support for the involvement of mGluR5 in ASD, encourage the study of mGluR5 in larger samples, and suggest a therapeutic potential for agents targeting the mGluR5 in autism (Mehta et al, 2011; Silverman et al, 2010).
Keywords: mGluR5 Receptors, Autism Spectrum Disorder, PET Imaging
Disclosure: Nothing to Disclose.

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