In vivo metabotropic glutamate receptor type 5 abnormalities localize the epileptogenic zone in mesial temporal lobe epilepsy

Objective Surgical specimens from patients with mesial temporal lobe epilepsy (MTLE) show abnormalities in tissue concentrations of metabotropic glutamate receptor type 5 (mGluR5). To clarify whether these abnormalities are specific to the epileptogenic zone (EZ), we characterized in vivo whole-brain mGluR5 availability in MTLE patients using positron emission tomography (PET) and [C-11]ABP688, a radioligand that binds specifically to the mGluR5 allosteric site. Methods Thirty-one unilateral MTLE patients and 30 healthy controls underwent [C-11]ABP688 PET. We compared partial volume corrected [C-11]ABP688 nondisplaceable binding potentials (BPND) between groups using region-of-interest and whole-brain voxelwise analyses. [F-18]Fluorodeoxyglucose (FDG) PET was acquired in 15 patients, for whom we calculated asymmetry indices of [C-11]ABP688 BPND and [F-18]FDG uptake to compare lateralization and localization differences. Results [C-11]ABP688 BPND was focally reduced in the epileptogenic hippocampal head and amygdala (p < 0.001). Patients with hippocampal atrophy showed more extensive abnormalities, including the ipsilateral temporal neocortex (p = 0.006). [C-11]ABP688 BPND showed interhemispheric differences of higher magnitude and discriminated the epileptogenic structures more accurately when compared to [F-18]FDG uptake, which showed more widespread hypometabolism. Among 23 of 25 operated patients with >1 year of follow-up, 13 were seizure-free (Engel Ia) and showed significantly lower [C-11]ABP688 BPND in the ipsilateral entorhinal cortex. Interpretation [C-11]ABP688 PET provides a focal biomarker for the EZ in MTLE with higher spatial accuracy compared to [F-18]FDG PET. Focally reduced mGluR5 availability in the EZ might reflect receptor internalization or conformational changes in response to excessive extracellular glutamate, supporting a potential role for mGluR5 as therapeutic target in human MTLE. Ann Neurol 2019; 1-11 ANN NEUROL 2019;85:218-228.