DOI: 10.5281/zenodo.4101172
title: Reduced metabotropic glutamate receptor subtype 5 in men with fragile X syndrome

description: While several techniques exist to estimate the concentration of glutamate in the living brain, including magnetic resonance imaging (MRI) and brain biopsy, positron emission tomography (PET) uniquely provides the optimal means to measure the metabotropic glutamate receptors subtype 5 (mGluR<sub>5</sub>s). For these reasons, radiotracers that bind to mGluR<sub>5</sub> in the living brain and can be visualized with PET are promising tools to quantify the density and the distribution of mGluR<sub>5</sub>s in humans with FXS. <strong>Materials and Methods</strong> <em>Participants</em> All scans occurred between 1 PM and 3 PM to avoid the possible effects of diurnal variations on mGluR<sub>5</sub> (DeLorenzo C et al. 2017; Castañeda TR et al. 2004; Fuller PM et al. 2006; Meng T et al. 2015). Participants with fragile X syndrome (FXS), fragile X syndrome allele size mosaiscism (FXS-M), premutation of the fragile X gene (PM), autism spectrum disorder (ASD), and typical development (TD) underwent positron emission tomography to measure the density and the distribution of metabotropic glutamate receptors subtype 5 (mGluR<sub>5</sub>) in the brain. Participants from the Institute for Neurodegenerative Disorders (IND), New Haven, Connecticut, USA, included 7 men with FXS aged 22.3 to 33.6 (27.1+4.7) years, a man with FXS-M aged 56.6 years, and a women with PM and TD aged 56.3 years. For the men with FXS the height ranged from 67 to 74 (70.33+3.27) inches, the weight ranged from 154 to 285 (203.5+49.61) pounds, and the BMI ranged from 22.0 to 36.6 (28.8+5.7). The man with FXS-M was 70 inches in height, 238 pounds in weight, and had a BMI of 34.1. The woman with PM TD was 65.6 inches in height, 258 pounds, and 42.3 BMI (Table S2). The man with FXS-M was allele size mosaic (PM 181 CGGs, 20% methylated, and the full-mutation allele 100% methylated). The men with FXS read below the first grade level and the man with FXS-M read at the eighth grade level. All participants from IND were non-Hispanic adults (Table S4). Participants from Johns Hopkins University (JHU), Baltimore, Maryland, USA included 4 men with FXS,aged 19 to 41 (27.6+9.43) years, 6 men with ASD aged 18 to 22 (20+2.1) years, and 3 individuals (1 man and 2 women) with TD aged 19 to 24 (20.67+2.89) years (Table S3). Table S1 lists the concomitant medications of participants from the Institute for Neurodegenerative Disorders (IND), New Haven, Connecticut, USA. The genetic and neurobehavioral assessments are presented for participants from the Institute for Neurodegenerative Disorders (IND), New Haven, Connecticut, USA, in Table S4 and for participants from the Johns Hopkins University (JHU), Baltimore, Maryland, USA in Table S5. Clinically participants JHUFXS1 and JHUFXS2 did not exhibit ASD. Participant JHUFXS1 withdrew from the study for a family emergency before neurobehavioral testing including symptoms of ASD (Lord et al., 2012) was accomplished. Because of his age participant JHUFSX2 was adminiered module 4 of the ADOS (Lord et al., 2012). Due to his limited speech a lower module would likely appropriately indicate the absence of autism. In other words, the symptoms demonstrated by module 4 of the ADOS (Lord et al. 2012) likely reflect an artifact of the incorrect administration of a module for higher functioning individuals. At JHU recruiting participants was challenging because research with positron emission tomography (PET) had not previously been conducted on people with FXS. Therefore, all participants with FXS at JHU were recruited regardless of the presence of ASD. . The positron emission tomography data and analysis are presented for participants from the Institute for Neurodegenerative Disorders in Table S4 and for participants from the Johns Hopkins University in Table S5. The authors thank Flora Tassone, Ph.D., Department of Biochemistry and Molecular Medicine, School of Medicine, UC Davis Health, Sacramento, California, for providing genetic and protein data about participants. <strong>Disclosures: </strong>We disclose the unlabeled/unapproved use of 3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-[<sup>11</sup>C]methyl-oxime ([<sup>11</sup>C]ABP688)
description: This research was made possible by a Radiology BRidge/Development Funding Initiative to STimulate and Advance Research (RAD BriteStar Bridge) Award from the Johns Hopkins University School of Medicine, Baltimore, Maryland, to JRB; the Intellectual & Developmental Disabilities Research Center (U54 HD079123), Kennedy Krieger Institute, Johns Hopkins Medical Institutions. Baltimore, Maryland, to JRB; and the Johns Hopkins Institute for Clinical and Translational Research (ICTR), Johns Hopkins University School of Medicine, Baltimore, Maryland, to JRB, which is funded in part by Grant Number UL1 TR003098 from the National Center for Advancing Translational Sciences (NCATS) a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of the Johns Hopkins ICTR, NCATS or NIH.
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