Introduction
Epilepsy is a heterogeneous collection of neurological diseases characterised clinically by recurrent seizures. Pre-clinical models implicate derangements in ligand-gated receptor-mediated neurotransmission in seizure generation and termination. In this thesis, the author quantified activated N-methyl D-aspartate- and opioid peptide receptor availability in adults with focal epilepsy.
Methods
This thesis consists of three positron emission tomography (PET) studies of adults with focal epilepsy, using [18F]GE-179 (activated NMDA receptors) and [11C]diprenorphine (DPN; opioid receptors) radioligands. A novel resolution-recovery technique, Structural Functional Synergistic – Resolution Recovery (SFS-RR), was applied to pre-existing paired [11C]DPN PET datasets acquired from adults with temporal lobe epilepsy (TLE). Activated NMDA receptor availability was quantified in adults with frequent interictal epileptiform discharges (IEDs), by regional compartmental modelling and model-free voxelwise analyses. Statistical parametric mapping was used to identify significant differences in volumes-of-distribution (VT) between populations. Results
[18F]GE-179 had good brain extraction with a relatively homogeneous distribution and moderately-paced kinetics in grey matter. The two brain compartments, four rate-constants model best described the radioligand’s kinetics in grey matter. Global increases in [18F]GE-179 VT were seen for seven of 11 participants with frequent IEDs. Focal increases in [18F]GE-179 VT of up to nearly 24% were also identified for three of the 11 participants. A post-ictal increase in [11C]DPN VT was identified in the ipsilateral parahippocampal gyrus.
Discussion
This first-in-man evaluation of [18F]GE-179 evidenced several properties that are desirable in PET radioligands, but the specificity of binding requires further characterisation. The results suggest focal increases in activated NMDA receptor availability in participants with refractory focal epilepsy, and also post-ictal increases in opioid peptide availability in the parahippocampal gyrus in TLE. Both findings may have pathophysiological relevance, and illustrate the potential of quantitative ligand PET with advanced post-processing to investigate changes in inhibitory and excitatory receptor systems in the epilepsies in vivo.