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.

Reduced uptake of [11C]‐ABP688, a PET tracer for metabolic glutamate receptor 5 in hippocampus and amygdala in Alzheimer’s dementia

“…Findings in frontotemporal dementia, where a reduction in mGluR5 binding overlaps with reductions in FDG‐PET in frontotemporal as well as subcortical regions, support this view further (Leuzy et al, 2016). Also, our results of higher mGLUR5 binding being associated with a better cognitive performance in several tests point in this direction.…”

G-Protein-Coupled Receptors in CNS: A Potential Therapeutic Target for Intervention in Neurodegenerative Disorders and Associated Cognitive Deficits

“…Moreover, the mGluR5 and NMDA receptors are colocalized in cortical regions of the brain and are also involved in the formation of receptor-dependent synaptic plasticity [46]. A recent study showed mGluR5 decreases in the paralimbic cortex region of FTD patients and may lead to the neurodegeneration observed [47]. Finally, mGluR5 activation enhances NMDA receptor action, while inhibition of the receptor blocks NMDA receptors [48].…”

Neurotransmitter deficits from frontotemporal lobar degeneration

“…6 B) ( Gascon et al , 2014 ). Using the ligand 11 C-ABP688, PET of patients with bvFTD found reduced availability of metabotropic glutamate receptors (mGluR5) in the frontal and temporal lobes, basal ganglia and thalamus ( Leuzy et al , 2016 ). However, one study found that post-mortem levels of metabotropic glutamate receptors type 1 and 5 (mGluR1 and 5) are increased in the frontal cortex ( Dalfo et al , 2005 ).…”