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Title: PET studies of neurotransmission in temporal lobe epilepsy
Author: Riano Barros, Daniela Alexandra
ISNI:       0000 0005 0733 6655
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
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Introduction: Epilepsy, defined as the recurrence of unprovoked seizures, is one of the commonest serious conditions in neurology. The World Health Organisation (WHO) estimates a prevalence of 50 million people worldwide, with a temporal lobe focus being the commonest cause of complex partial seizures. Patients with temporal lobe epilepsy (TLE) often have reduced GABAA receptors at their seizure focus, and poor memory performance. Blockade of GABAA receptors containing alpha5 subunits is promnestic. Animal models have also demonstrated alterations in cannabinoid type 1 (CB1) receptor availability in response to seizures. The studies presented in this thesis were designed to first determine the reliability of measurement with two novel PET tracers for the expression of alpha5 subunits of GABAA receptors ([11C]Ro15 4513) and CB1 receptors ([11C]MePPEP). These were then used in human TLE to try and elucidate mechanisms of memory impairment and minimally invasive characterisation of the seizure focus. Methods: Adult healthy volunteers underwent paired scans with [11C]Ro15 4513 (GABAA alpha5 receptor partial inverse agonist) and [11C]MePPEP (CB1 receptor mixed inverse agonist and antagonist). Test-retest variability was characterised for both radiotracers with quantification in regions spanning high and low receptor concentrations by regional compartmental modelling and a variety of regional and voxel-wise model-free analyses (spectral analysis and variants). Semiquantification with modified standard uptake values (mSUVs), in widespread clinical use, was also explored. In the clinical studies, healthy volunteers were compared with TLE patients using Statistical Parametric Mapping software. Paired post-ictal and interictal studies were obtained with [11C]MePPEP to determine changes in response to seizures. Single PET scans were obtained with [11C]Ro15 4513 to determine changes in relationship to memory impairments. Results: [11C]Ro15 4513 could be reliably quantified with voxel-wise spectral analysis, and the simplified reference tissue model, but not mSUVs or compartmental models. For [11C]MePPEP, voxel-wise spectral analysis, a one tissue compartment model and simple mSUVs were the most reliable methods in controls, while preserving between-region differences. CB1 availability in TLE was higher, at the group level, in the ipsilateral temporal lobe in post- ictal scans than in controls, and negatively correlated with time since last seizure. In individual patients, however, focal increases were not consistently found in the epileptogenic temporal lobe. [11C]Ro15 4513 scans could be obtained in 12 patients but have not yet been fully analysed. Discussion: I demonstrated that two novel PET tracers can be reliably quantified, using a much larger cohort and a much greater variety of methods than available in the literature in the case of [11C]MePPEP, and performing such an analysis for the first time for [11C]Ro15 4513. This laid the foundation for the clinical study of CB1 receptor availability in TLE patients. The hypothesis of an upregulation of this inhibitory G-protein coupled receptor type in response to single spontaneous seizures could be confirmed, but the method was not so far useful in individual patients. [11C]Ro15 4513 PET holds promise for the investigation of the mechanisms of memory impairment in TLE.
Supervisor: Hammers, Alexander; Koepp, Matthias; Brooks, David Sponsor: Medical Research Council ; Neurodis Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral