Galovic, Marian; (2021) Measuring NMDA receptors in vivo using [¹⁸F]GE-179 PET in health and disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Background: N-methyl-D-aspartate receptors (NMDAR) are important glutamatergic ion channels in the brain. Studying the functional activation of NMDAR in vivo in humans has not been possible until recently. / Methods: We used positron emission tomography (PET) with [18F]GE-179, a novel radioligand binding inside the open NMDAR channel, to assess the in vivo activation of NMDAR. We developed methodology for quantification of ligand binding (Project 1) that did not require arterial sampling and was then applied to study NMDAR activation in aging (n=29, Project 2), epilepsy (n=26, Project 3), and Anti-NMDAR encephalitis (n=5, Project 4). / Results: In Project 1, we validated a method for kinetic modelling using an imagederived input function and serial venous samples. This approach provided unbiased estimates of ligand volume of distribution (VT) that were highly correlated (r=0.95, p<0.001) with the gold standard, an arterial input function. In Project 2, we observed increased tracer uptake related to aging in healthy individuals (VT increase of 0.6 per 10 years, p=0.04), particularly in bilateral hippocampi, temporo-parieto-occipital junctions, dorsolateral prefrontal cortex, and striata. In people with epilepsy, the age-related increase in VT (1.4 per 10 years, p=0.006) was most pronounced in the striatum and thalamus. In Project 3, we found reduced interictal ligand uptake in epilepsy that was related to longer disease duration (VT decrease of 1.6 per 10 years, p=0.004), spatially widespread and bihemispheric. Regional uptake was increased in those taking lacosamide and after anterior temporal lobe resection. In Project 4, we observed decreased ligand uptake in Anti-NMDAR encephalitis with persisting Anti-GluN1-antibodies (mean VT 6.2 in cases vs. 8.8 in healthy volunteers, p=0.02), particularly in bilateral anterior temporal and superior parietal lobes. / Conclusions: [18F]GE-179 PET is useful to detect altered NMDAR function. We observed increased NMDAR activation in aging and decreased activation in interictal epilepsy and antibody-positive Anti-NMDAR encephalitis.

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