In vivo characterization of metabotropic glutamate receptor type 5 abnormalities in behavioral variant FTD.

Abstract

Although the pathogenesis underlying behavioral variant frontotemporal dementia (bvFTD) has yet to be fully understood, glutamatergic abnormalities have been hypothesized to play an important role. The aim of the present study was to determine the availability of the metabotropic glutamate receptor type 5 (mGluR5) using a novel positron emission tomography (PET) radiopharmaceutical with high selectivity for mGluR5 ([(11)C]ABP688) in a sample of bvFTD patients. In addition, we sought to determine the overlap between availability of mGluR5 and neurodegeneration, as measured using [(18)F]FDG-PET and voxel-based morphometry (VBM). Availability of mGluR5 and glucose metabolism ([(18)F]FDG) were measured in bvFTD (n = 5) and cognitively normal (CN) subjects (n = 10). [(11)C]ABP688 binding potential maps (BPND) were calculated using the cerebellum as a reference region, with [(18)F]FDG standardized uptake ratio maps (SUVR) normalized to the pons. Grey matter (GM) concentrations were determined using VBM. Voxel-based group differences were obtained using RMINC. BvFTD patients showed widespread decrements in [(11)C]ABP688 BPND throughout frontal, temporal and subcortical areas. These areas were likewise characterized by significant hypometabolism and GM loss, with overlap between reduced [(11)C]ABP688 BPND and hypometabolism superior to that for GM atrophy. Several regions were characterized only by decreased binding of [(11)C]ABP688. The present findings represent the first in vivo report of decreased availability of mGluR5 in bvFTD. This study suggests that glutamate excitotoxicity may play a role in the pathogenesis of bvFTD and that [(11)C]ABP688 may prove a suitable marker of glutamatergic neurotransmission in vivo.

• Authors: Antoine Leuzy, Eduardo Rigon Zimmer, Jonathan Dubois, Jens Pruessner, Cory Cooperman, Jean-Paul Soucy, Alexey Kostikov, Esther Schirmaccher, René Désautels, Serge Gauthier, Pedro Rosa-Neto
• Journal: Brain structure & function (Brain Struct Funct) Vol. 221 Issue 3 Pg. 1387-402 (Apr 2016) ISSN: 1863-2661 [Electronic] Germany
• PMID: 25596865 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-(6-methylpyridin-2-ylethynyl)cyclohex-2-enone-O-methyloxime
• Carbon Radioisotopes
• GRM5 protein, human
• Oximes
• Pyridines
• Receptor, Metabotropic Glutamate 5
• Glucose

Topics

• Aged
• Brain (drug effects, metabolism)
• Carbon Radioisotopes
• Female
• Frontotemporal Dementia (diagnostic imaging, metabolism)
• Glucose (metabolism)
• Humans
• Male
• Middle Aged
• Oximes (administration & dosage)
• Positron-Emission Tomography (methods)
• Pyridines (administration & dosage)
• Receptor, Metabotropic Glutamate 5 (antagonists & inhibitors, metabolism)