PET Studies of Neurotransmission in Temporal Lobe Epilepsy

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.Open Acces

Acute induction of anxiety in humans by delta-9-tetrahydrocannabinol related to amygdalar cannabinoid-1 (CB1) receptors.

Use of Cannabis, the most widely used illicit drug worldwide, is associated with acute anxiety, and anxiety disorders following regular use. The precise neural and receptor basis of these effects have not been tested in man. Employing a combination of functional MRI (fMRI) and positron emission tomography (PET), we investigated whether the effects of delta-9-tetrahydrocannabinol (delta-9-THC), the main psychoactive ingredient of cannabis, on anxiety and on amygdala response while processing fearful stimuli were related to local availability of its main central molecular target, cannabinoid-1 (CB1) receptors in man. Fourteen healthy males were studied with fMRI twice, one month apart, following an oral dose of either delta-9-THC (10 mg) or placebo, while they performed a fear-processing task. Baseline availability of the CB1 receptor was studied using PET with [(11)C]MePPEP, a CB1 inverse agonist radioligand. Relative to the placebo condition, delta-9-THC induced anxiety and modulated right amygdala activation while processing fear. Both these effects were positively correlated with CB1 receptor availability in the right amygdala. These results suggest that the acute effects of cannabis on anxiety in males are mediated by the modulation of amygdalar function by delta-9-THC and the extent of these effects are related to local availability of CB1 receptors

Initial Evaluation of 18F-GE-179, a Putative PET Tracer for Activated N-Methyl D-Aspartate Receptors

International audienceN-methyl d-aspartate (NMDA) ion channels play a key role in a wide range of physiologic (e.g., memory and learning tasks) and pathologic processes (e.g., excitotoxicity). To date, suitable PET markers of NMDA ion channel activity have not been available. (18)F-GE-179 is a novel radioligand that selectively binds to the open/active state of the NMDA receptor ion channel, displacing the binding of (3)H-tenocyclidine from the intrachannel binding site with an affinity of 2.4 nM. No significant binding was observed with 10 nM GE-179 at 60 other neuroreceptors, channels, or transporters. We describe the kinetic behavior of the radioligand in vivo in humans. METHODS: Nine healthy participants (6 men, 3 women; median age, 37 y) each underwent a 90-min PET scan after an intravenous injection of (18)F-GE-179. Continuous arterial blood sampling over the first 15 min was followed by discrete blood sampling over the duration of the scan. Brain radioactivity (KBq/mL) was measured in summation images created from the attenuation- and motion-corrected dynamic images. Metabolite-corrected parent plasma input functions were generated. We assessed the abilities of 1-, 2-, and 3-compartment models to kinetically describe cerebral time-activity curves using 6 bilateral regions of interest. Parametric volume-of-distribution (VT) images were generated by voxelwise rank-shaping regularization of exponential spectral analysis (RS-ESA). RESULTS: A 2-brain-compartment, 4-rate-constant model best described the radioligand's kinetics in normal gray matter of subjects at rest. At 30 min after injection, 37% of plasma radioactivity represented unmetabolized (18)F-GE-179. The highest mean levels of gray matter radioactivity were seen in the putamina and peaked at 7.5 min. A significant positive correlation was observed between K1 and VT (Spearman ρ = 0.398; P = 0.003). Between-subject coefficients of variation of VT ranged between 12% and 16%. Voxelwise RS-ESA yielded similar VTs and coefficients of variation. CONCLUSION: (18)F-GE-179 exhibits high and rapid brain extraction, with a relatively homogeneous distribution in gray matter and acceptable between-subject variability. Despite its rapid peripheral metabolism, quantification of (18)F-GE-179 VT is feasible both within regions of interest and at the voxel level. The specificity of (18)F-GE-179 binding, however, requires further characterization with in vivo studies using activation and disease models

Assessment of clinical outcomes of medicinal cannabis therapy for depression: analysis from the UK Medical Cannabis Registry.

BACKGROUND Although pre-clinical experiments associate cannabinoids with reduced depressive symptoms, there is a paucity of clinical evidence. This study aims to analyze the health-related quality of life changes and safety outcomes in patients prescribed cannabis-based medicinal products (CBMPs) for depression. METHODS A series of uncontrolled cases from the UK Medical Cannabis Registry were analyzed. The primary outcomes were changes from baseline in the Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), Sleep Quality Scale (SQS), and EQ-5D-5 L at 1, 3, and 6 months. Secondary outcomes included adverse events incidence. RESULTS 129 patients were identified for inclusion. Median PHQ-9 at baseline was 16.0 (IQR: 9.0-21.0). There were reductions in PHQ-9 at 1-month (median: 8.0; IQR: 4.0-14.0; p < 0.001), 3-months (7.0; 2.3-12.8; p < 0.001), and 6-months (7.0; 2.0-9.5; p < 0.001). Improvements were also observed in GAD-7, SQS, and EQ-5D-5L Index Value at 1, 3, and 6 months (p < 0.050). 153 (118.6%) adverse events were recorded by 14.0% (n = 18) of participants, 87% (n = 133) of which were mild or moderate. CONCLUSION CBMP treatment was associated with reductions in depression severity at 1, 3, and 6 months. Limitations of the study design mean that a causal relationship cannot be proven. This analysis provides insights for further study within clinical trial settings