@article{57bda7f37cf84fb3aecee7be41fa187e,
title = "Reduced expression of cerebral metabotropic glutamate receptor subtype 5 in men with fragile x syndrome",
abstract = "Glutamatergic receptor expression is mostly unknown in adults with fragile X syndrome (FXS). Favorable behavioral effects of negative allosteric modulators (NAMs) of the metabotropic glutamate receptor subtype 5 (mGluR5) in fmr1 knockout (KO) mouse models have not been confirmed in humans with FXS. Measurement of cerebral mGluR5 expression in humans with FXS exposed to NAMs might help in that effort. We used positron emission tomography (PET) to measure the mGluR5 density as a proxy of mGluR5 expression in cortical and subcortical brain regions to confirm target engagement of NAMs for mGluR5s. The density and the distribution of mGluR5 were measured in two independent samples of men with FXS (N = 9) and typical development (TD) (N = 8). We showed the feasibility of this complex study including MRI and PET, meaning that this challenging protocol can be accomplished in men with FXS with an adequate preparation. Analysis of variance of estimated mGluR5 expression showed that mGluR5 expression was significantly reduced in cortical and subcortical regions of men with FXS in contrast to age-matched men with TD.",
keywords = "3-[F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([F]FPEB), Binding potential, Caudate nucleus, FMR1 gene, Fragile X Mental Retardation Protein (FMRP), Genetic mutation, Magnetic resonance imaging (MRI), Mosaicism, Neuropsychological testing, Positron emission tomography (PET)",
author = "Bra{\v s}i{\'c}, {James R.} and Ayon Nandi and Russell, {David S.} and Danna Jennings and Olivier Barret and Anil Mathur and Keith Slifer and Thomas Sedlak and Martin, {Samuel D.} and Zabecca Brinson and Pankhuri Vyas and Seibyl, {John P.} and Berry-Kravis, {Elizabeth M.} and Wong, {Dean F.} and Budimirovic, {Dejan B.}",
note = "Funding Information: 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 with the assistance of DFW; the Intellectual & Developmental Disabilities Research Center (U54 HD079123), Kennedy Krieger Institute, and 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.The authors thank the patients and families for their participation and dedication to these studies; they are the inspiration for our efforts at improving treatments. The authors thank the FORWARD Database and Registry of the National Fragile X Foundation (NFXF) funded by the Centers for Disease Control and Prevention (CDC), Atlanta, Georgia, for referral of participants. The authors thank the teams of the Institute of Neurodegenerative Disorders, the Positron Emission Tomography (PET) Radiotracer Service Center, and the Research Magnetic Resonance Imaging (MRI) Service Center of the Johns Hopkins University School of Medicine for conducting the scans. The authors thank Hiroto Kuwabara for PET analysis. The authors acknowledge Rohan Panaparambil and Mathew Shneyderman for their guidance to revise the paper. The authors thank Brian Hwang for contributing to the graphical abstract. Earlier versions of this article were presented at the 2020 Annual Meeting, Society of Nuclear Medicine and Molecular Imaging, 11–14 July 2020 [86], and the World Molecular Imaging Congress 2020. Funding Information: Funding: 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 with the assistance of DFW; the Intellectual & Developmental Disabilities Research Center (U54 HD079123), Kennedy Krieger Institute, and 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. Funding Information: Acknowledgments: The authors thank the patients and families for their participation and dedication to these studies; they are the inspiration for our efforts at improving treatments. The authors thank the FORWARD Database and Registry of the National Fragile X Foundation (NFXF) funded by the Centers for Disease Control and Prevention (CDC), Atlanta, Georgia, for referral of participants. The authors thank the teams of the Institute of Neurodegenerative Disorders, the Positron Emission Tomography (PET) Radiotracer Service Center, and the Research Magnetic Resonance Imaging (MRI) Service Center of the Johns Hopkins University School of Medicine for conducting the scans. The authors thank Hiroto Kuwabara for PET analysis. The authors acknowledge Rohan Panaparambil and Mathew Shneyderman for their guidance to revise the paper. The authors thank Brian Hwang for contributing to the graphical abstract. Earlier versions of this article were presented at the 2020 Annual Meeting, Society of Nuclear Medicine and Molecular Imaging, 11–14 July 2020 [86], and the World Molecular Imaging Congress 2020. Funding Information: Four men with FXS (mean age 28 ± 9, range 19–41 years) were recruited from the Kennedy Krieger Institute, Baltimore, Maryland, and Rush University Medical Center, including referrals from the Fragile X Online Registry With Accessible Research Database (FORWARD) of the National Fragile X Foundation (NFXF) funded by the Centers for Disease Control and Prevention (CDC), Atlanta, Georgia. The results of two of the four men with FXS (mean age 25.5 ± 2.1, range 24–27) who completed PET scans were reported in this article. Findings were compared and contrasted with five age-matched historical control men with TD who had already completed similar protocols (mean age 29.6 ± 6.02, range 24–39 years) [25,30]. Clinical and demographic data confirmed that all participants met the criteria to receive the adult dose of 185 MBqs (5 mCis) of [18F]FPEB [55]. Publisher Copyright: {\textcopyright} 2020 by the authors. Licensee MDPI, Basel, Switzerland.",
year = "2020",
month = dec,
doi = "10.3390/brainsci10120899",
language = "English",
volume = "10",
pages = "1--17",
journal = "Brain Sciences",
issn = "2076-3425",
number = "12",
}