MEASUREMENT OF CEREBRAL EXPRESSION OF METABOTROPIC GLUTAMATE RECEPTOR SUBTYPE 5 IN AUTISM SPECTRUM DISORDER AND FRAGILE X SYNDROME

Abstract

Although dysregulation of metabotropic glutamate receptor subtype 5 (mGluR5)-mediated signaling has consistently been confirmed in preclinical and clinical studies of fragile X syndrome (FXS) and other subtypes of autism spectrum disorder (ASD), studies of mGluR5 expression yielded conflicting findings. Clinical trials to modulate mGluR5-mediated signaling have been hindered by the absence of a tool to measure mGluR5 expression in the living human brain. We sought to measure mGluR5 expression in people with FXS, ASD, and typical development (TD). Two teams of investigators independently administered 3-[18F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([18F]FPEB), a novel, specific mGluR5 positron emission tomography (PET) ligand to quantitatively measure the density and the distribution of mGluR5s, to participants of both sexes with ASD and TD and to men with FXS including 1 man with FXS allele size mosaicism (FXS-M). Behavioral psychologists provided mock scanner training to participants with FXS before undergoing scans. In order to maximize the size effect, we report the combined sample of participants with ASD (N = 7, age [mean ± SD] 19.71 years ± 2.06), FXS (N = 10, age 29.7 years ± 10.39), and TD (N = 19, age 34.89 years ± 14.57). In contrast to participants with TD, mGluR5 expression was increased in cortical regions of participants with ASD and reduced in all regions of men with FXS. For example, mGluR5 uptake (mean ± SD) in the temporal lobe was 1.72 ± 0.65 (95% CI, 1.18-2.26) for FXS, 2.97 ± 1.04 (95% CI, 2.47-3.47) for TD, and 4.01 ± 0.63 (95% CI, 3.42-4.6) for ASD. Additionally, mGluR5 uptake in deep nuclei was lower in participants with FXS than in participants with ASD and TD with equivalent uptake in ASD and TD. For example, mGluR5 uptake in the thalamus was 0.87 ± 0.31 (95% CI, 0.65-1.09) for FXS, 1.52 ± 0.47 (95% CI, 1.29-1.75) for TD, and 1.5 ± 0.17 (95% CI, 1.34-1.66) for ASD. PET with [18F]FPEB with mock scanner training by behavioral psychologists provides a promising tool to measure cerebral mGluR5 expression of people with FXS and other subtypes of ASD. Expression of mGluR5 was reduced throughout the brains of men with FXS and elevated in cortical regions of people with ASD. This protocol provides the means to measure mGluR5 expression in people with FXS and other subtypes of ASD for rigorous clinical trials.