Abstract Details

Title Reduced Metabotropic Glutamate Receptor Subtype 5 in Fragile X Syndrome

Topic Child Neurology and Developmental Neurology

Presentation(s) Child Neurology and Developmental Neurology Posters (7:00 AM-5:00 PM)

Poster/Presentation
Number 016

Objective To establish the feasibility of measurement of the expression of the metabotropic glutamate receptor subtype 5 (mGluR₅) in men with fragile X syndrome (FXS).

Background Dysfunction of the group 1 metabotropic glutamatergic pathways leading to increased downstream signaling cascades including the mammalian target of rapamycin (mTOR) and the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) cascades lead to increased protein synthesis in the fmr1 knockout (KO) mouse model of FXS. Although administration of mGlu5₅negative allosteric modulators (NAMs) ameliorated neurobehavioral symptoms in the KO mouse model, multiple clinical trials of NAMs failed to improve neurobehavioral symptoms of humans with FXS. The presence of an adequate tool to measure mGluR₅ expression in humans with FXS will enhance clinical trials.

Design/Methods Investigators at two institutions independently conducted comparable experiments. Men with FXS (N=9) and adults of both sexes with typical development (TD) (N=10) underwent positron emission (PET) after the administration of 3-[¹⁸F]fluoro-5-(2-pyridinylethynyl) ([¹⁸F]FPEB), a novel, specific radioligand to provide quantitative measurements of the density and the distribution of mGluR₅s. mGluR5s density as a proxy of the mGluR₅ expression was estimated by comparing radiotracer uptake in regions of interest (anterior cingulate, caudate, medial temporal, parietal, putamen, and thalamus) with the uptake in the cerebellum, a reference region.

Results mGluR5s expression was significantly reduced in the anterior cingulate, medial temporal, parietal, putamen, and thalamus of men with FXS in contrast to healthy adults with TD in the combined samples from both institutions.

Conclusions

The proposed PET protocol provides a feasible tool to quantitatively measure mGluR₅ expression in adults with FXS.

mGluR₅ expression is significantly reduced in cortical and limbic regions of men with FXS, a possible explanation for the deficits in the neurobehavioral symptoms of men with FXS.

The proposed protocol provides a tool to measure mGluR₅ expression for optimal clincal trials of novel interventions for FXS.

Authors/Disclosures
James R. Brasic, MD, F�鶹��ýӳ�� (Bellevue Hospital Center) PRESENTER	Dr. Brasic has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Image Guided Therapy Research Institute. Dr. Brasic has received personal compensation in the range of $500-$4,999 for serving as a Consultant for One World, Inc.. Dr. Brasic has received personal compensation in the range of $500-$4,999 for serving as an officer or member of the Board of Directors for Society of Nuclear Medicine and Molecular Imaging. Dr. Brasic has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Multidisciplinary Digital Publishing Institute. Dr. Brasic has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Gerson Lehman Group, Inc..
Ayon Nandi (JHU)	No disclosure on file
David S. Russell, MD, PhD (Invicro)	Dr. Russell has received personal compensation for serving as an employee of Invicro. Dr. Russell has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Neurocrine. The institution of Dr. Russell has received research support from Biogen. The institution of Dr. Russell has received research support from Roche. The institution of Dr. Russell has received research support from Voyager. The institution of Dr. Russell has received research support from Eisai. The institution of Dr. Russell has received research support from Neuraly. The institution of Dr. Russell has received research support from Michael J. Fox Foundation. The institution of Dr. Russell has received research support from National Institutes for Health. The institution of Dr. Russell has received research support from Eli Lilly. The institution of Dr. Russell has received research support from Aprinoia.
Danna L. Jennings, MD (Denali Therapeutics)	Dr. Jennings has received personal compensation for serving as an employee of Denali Therapeutics . Dr. Jennings has received stock or an ownership interest from Denali Therapeutics.
Olivier Barret (MIRCEN)	No disclosure on file
	No disclosure on file
Keith Slifer (Kennedy Krieger Institute)	The institution of Keith Slifer has received research support from National Heart, Lung, and Blood. Keith Slifer has received publishing royalties from a publication relating to health care.
Thomas Sedlak (Johns Hopkins School of Medicine)	Thomas Sedlak has nothing to disclose.
	No disclosure on file
	No disclosure on file
	No disclosure on file
John P. Seibyl, MD	Dr. Seibyl has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Invicro. Dr. Seibyl has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biogen. Dr. Seibyl has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Life Molecular Imaging. Dr. Seibyl has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Roche. Dr. Seibyl has received stock or an ownership interest from Invicro.
Elizabeth M. Berry-Kravis, MD, PhD (Rush University Medical Center)	The institution of Dr. Berry-Kravis has received research support from NIH. The institution of Dr. Berry-Kravis has received research support from Ionis. The institution of Dr. Berry-Kravis has received research support from Zynerba. The institution of Dr. Berry-Kravis has received research support from Roche. The institution of Dr. Berry-Kravis has received research support from CDC. The institution of Dr. Berry-Kravis has received research support from FRAXA Research Foundation. The institution of Dr. Berry-Kravis has received research support from GeneTx. The institution of Dr. Berry-Kravis has received research support from Angelman Syndrome Foundation. The institution of Dr. Berry-Kravis has received research support from Acadia. The institution of Dr. Berry-Kravis has received research support from Ultragenyx. The institution of Dr. Berry-Kravis has received research support from Mallinckrodt. The institution of Dr. Berry-Kravis has received research support from Together Strong Foundation. The institution of Dr. Berry-Kravis has received research support from Zevra. The institution of Dr. Berry-Kravis has received research support from Taysha. The institution of Dr. Berry-Kravis has received research support from Tetra. The institution of Dr. Berry-Kravis has received research support from Neuren.
	No disclosure on file
Dejan Budimirovic	No disclosure on file

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