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

• Published in: Annals of neurology Vol. 85; no. 2; pp. 218 - 228
• Main Authors: Lam, Jack, DuBois, Jonathan M., Rowley, Jared, González‐Otárula, Karina A., Soucy, Jean‐Paul, Massarweh, Gassan, Hall, Jeffery A., Guiot, Marie‐Christine, Rosa‐Neto, Pedro, Kobayashi, Eliane
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01-02-2019; Wiley Subscription Services, Inc
• Subjects: Abnormalities; Allosteric properties; Amygdala; Atrophy; Biomarkers; Brain; Cerebral hemispheres; Cortex (entorhinal); Epilepsy; Fluorine isotopes; Glutamic acid receptors (metabotropic); Head; Hemispheric laterality; Hippocampus; Hypometabolism; Internalization; Localization; Patients; Positron emission; Positron emission tomography; Seizures; Surgery; Temporal cortex; Temporal lobe; Therapeutic applications; Tomography
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.25404

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 [11C]ABP688, a radioligand that binds specifically to the mGluR5 allosteric site.
Methods
Thirty‐one unilateral MTLE patients and 30 healthy controls underwent [11C]ABP688 PET. We compared partial volume corrected [11C]ABP688 nondisplaceable binding potentials (BPND) between groups using region‐of‐interest and whole‐brain voxelwise analyses. [18F]Fluorodeoxyglucose (FDG) PET was acquired in 15 patients, for whom we calculated asymmetry indices of [11C]ABP688 BPND and [18F]FDG uptake to compare lateralization and localization differences.
Results
[11C]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). [11C]ABP688 BPND showed interhemispheric differences of higher magnitude and discriminated the epileptogenic structures more accurately when compared to [18F]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 [11C]ABP688 BPND in the ipsilateral entorhinal cortex.
Interpretation
[11C]ABP688 PET provides a focal biomarker for the EZ in MTLE with higher spatial accuracy compared to [18F]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.