We retrospectively examined the relationship between blood biomarkers, in particular the historical mean phenylalanine to tyrosine (Phe:Tyr) ratio, and cerebral glucose metabolism. We hypothesized ...that the historical mean Phe:Tyr ratio would be more predictive of cerebral glucose metabolism than the phenylalanine (Phe) level alone. We performed a retrospective case series analysis involving 11 adult classical phenylketonuria/hyperphenylalaninemia patients under the care of an Inherited Metabolic & Neuropsychiatry Clinic who had complained of memory problems, collating casenote data from blood biochemistry, and clinical
18
Ffluorodeoxyglucose positron emission tomography (
18
FFDG PET). The Phe:Tyr ratio was calculated for individual blood samples and summarized as historical mean Phe:Tyr ratio (Phe:Tyr) and historical standard deviation in Phe:Tyr ratio (SD-Phe:Tyr), for each patient. Visual analyses of
18
FFDG PET revealed heterogeneous patterns of glucose hypometabolism for eight patients.
18
FFDG PET standardized uptake was negatively correlated with Phe in a large cluster with peak localized to right superior parietal gyrus. Even larger clusters of negative correlation that encompassed most of the brain, with frontal peaks, were observed with Phe:Tyr, and SD-Phe:Tyr. Our case series analysis provides further evidence for the association between blood biomarkers, and cerebral glucose hypometabolism. Mean historical blood Phe:Tyr ratio, and its standard deviation over time, appear to be more indicative of global cerebral glucose metabolism in patients with memory problems than Phe.
Schoenberger and colleagues (Schoenberger et al. (2018) ACS Chem. Neurosci. 9, 298−305 ) recently reported attempts to demonstrate specific binding of the positron emission tomography (PET) ...radiotracer, 18FGE-179, to NMDA receptors in both rats and Rhesus macaques. GE-179 did not work as expected in animal models; however, we disagree with the authors’ conclusion that “the 18FGE-179 signal seems to be largely nonspecific”. It is extremely challenging to demonstrate specific binding for the use-dependent NMDA receptor intrachannel ligands such as 18FGE-179 in animals via traditional blocking, due to its low availability of target sites (B max ′). Schoenberger and colleagues anesthetized rats and Rhesus monkeys using isoflurane, which has an inhibitory effect on NMDA receptor function and thus would be expected to further reduce the B max ′. The extent of glutamate release achieved in the provocation experiments is uncertain, as is whether a significant increase in NMDA receptor channel opening can be expected under anesthesia. Prior data suggest that the uptake of disubstituted arylguanidine-based ligands such as GE-179 can be reduced by phencyclidine binding site antagonists, if injection is performed in the absence of ketamine and isoflurane anesthesia, e.g., with GE-179’s antecedent, CNS 5161 (Biegon et al. (2007) Synapse 61, 577−586 ), and with GMOM (van der Doef et al. (2016) J. Cereb. Blood Flow Metab. 36, 1111−1121 ). However, the extent of nonspecific uptake remains uncertain.
Previous positron emission tomography (PET) studies in refractory temporal lobe epilepsy (TLE) using the non-selective opioid receptor antagonist 11Cdiprenorphine (DPN) did not detect any changes in ...mesial temporal structures, despite known involvement of the hippocampus in seizure generation. Normal binding in smaller hippocampi is suggestive of increased receptor concentration in the remaining grey matter. Correction for partial-volume effect (PVE) has not been used in previous DPN PET studies. Here, we present PVE-corrected DPN-PET data quantifying post-ictal and interictal opioid receptor availability in humans with mTLE.
Eight paired datasets of post-ictal and interictal DPN PET scans and eleven test/retest control datasets were available from a previously published study on opioid receptor changes in TLE following seizures (Hammers et al., 2007a). Five of the eight participants with TLE had documented hippocampal sclerosis. Data were re-analyzed using regions of interest and a novel PVE correction method (structural functional synergistic-resolution recovery (SFS-RR); (Shidahara et al., 2012)). Data were denoised, followed by application of SFS-RR, with anatomical information derived via precise anatomical segmentation of the participants' MRI (MAPER; (Heckemann et al., 2010)). 11Cdiprenorphine volume-of-distribution (VT) was quantified in six regions of interest.
Post-ictal increases were observed in the ipsilateral fusiform gyri and lateral temporal pole. A novel finding was a post-ictal increase in 11CDPN VT relative to the interictal state in the ipsilateral parahippocampal gyrus, not observed in uncorrected datasets. As for voxel-based (SPM) analyses, correction for global VT values was essential in order to demonstrate focal post-ictal increases in 11CDPN VT.
This study provides further direct human in vivo evidence for changes in opioid receptor availability in TLE following seizures, including changes that were not evident without PVE correction. Denoising, resolution recovery and precise anatomical segmentation can extract valuable information from PET studies that would be missed with conventional post-processing procedures.
•SFS-RR is a novel partial-volume effect correction method for PET data.•Eight post-ictal and interictal 11Cdiprenorphine datasets were re-processed.•Comparison was made to eleven paired test-re-test datasets from healthy controls.•A post-ictal increase in VT was newly identified in the parahippocampal gyrus.•Resolution recovery can extract information from PET that would otherwise be missed.
The importance of the GABA-benzodiazepine receptor complex and its subtypes are increasingly recognised in addiction. Using the α1/α5 benzodiazepine receptor PET radioligand 11CRo15 4513, we ...previously showed reduced binding in the nucleus accumbens and hippocampus in abstinent alcohol dependence. We proposed that reduced 11CRo15 4513 binding in the nucleus accumbens was a marker of addiction whilst the reduction in hippocampus and positive relationship with memory was a consequence of chronic alcohol abuse. To examine this further we assessed 11CRo15 4513 binding in another addiction, opiate dependence, and used spectral analysis to estimate contributions of α1 and α5 subtypes to 11CRo15 4513 binding in opiate and previously acquired alcohol-dependent groups. Opiate substitute maintained opiate-dependent men (n=12) underwent an 11CRo15 4513 PET scan and compared with matched healthy controls (n=13). We found a significant reduction in 11CRo15 4513 binding in the nucleus accumbens in the opiate-dependent compared with the healthy control group. There was no relationship between 11CRo15 4513 binding in the hippocampus with memory. We found that reduced 11CRo15 4513 binding was associated with reduced α5 but not α1 subtypes in the opiate-dependent group. This was also seen in an alcohol-dependent group where an association between memory performance and 11CRo15 4513 binding was primarily driven by α5 and not α1 subtype. We suggest that reduced α5 levels in the nucleus accumbens are associated with addiction since we have now shown this in dependence to two pharmacologically different substances, alcohol and opiates.
•Lower 11CRo15 4513 binding is evident in the nucleus accumbens of opiate addicts.•This appears primarily due to lower levels of α5 subtype of the GABA-A receptor.•Lower 11CRo15 4513 binding is similarly found in alcoholism.•Lower levels of α5 GABA-A receptor in nucleus accumbens may underpin addiction.
Alteration of γ-aminobutyric acid "A" (GABA
) receptor-mediated neurotransmission has been associated with various neurological and psychiatric disorders.
CRo15-4513 is a PET ligand with high ...affinity for α5-subunit-containing GABA
receptors, which are highly expressed in limbic regions of the human brain (Sur et al., 1998). We quantified the test-retest reproducibility of measures of
CRo15-4513 binding derived from six different quantification methods (12 variants).
Five healthy males (median age 40 years, range 38-49 years) had a 90-min PET scan on two occasions (median interval 12 days, range 11-30 days), after injection of a median dose of 441 MegaBequerels of
CRo15-4513. Metabolite-corrected arterial plasma input functions (parent plasma input functions, ppIFs) were generated for all scans. We quantified regional binding using six methods (12 variants), some of which were region-based (applied to the average time-activity curve within a region) and others were voxel-based: 1) Models requiring arterial ppIFs - regional reversible compartmental models with one and two tissue compartments (2kbv and 4kbv); 2) Regional and voxelwise Logan's graphical analyses (Logan et al., 1990), which required arterial ppIFs; 3) Model-free regional and voxelwise (exponential) spectral analyses (SA; (Cunningham and Jones, 1993)), which also required arterial ppIFs; 4) methods not requiring arterial ppIFs - voxelwise standardised uptake values (Kenney et al., 1941), and regional and voxelwise simplified reference tissue models (SRTM/SRTM2) using brainstem or alternatively cerebellum as pseudo-reference regions (Lammertsma and Hume, 1996; Gunn et al., 1997). To compare the variants, we sampled the mean values of the outcome parameters within six bilateral, non-reference grey matter regions-of-interest. Reliability was quantified in terms of median absolute percentage test-retest differences (MA-TDs; preferentially low) and between-subject coefficient of variation (BS-CV, preferentially high), both compounded by the intraclass correlation coefficient (ICC). These measures were compared between variants, with particular interest in the hippocampus.
Two of the six methods (5/12 variants) yielded reproducible data (i.e. MA-TD <10%): regional SRTMs and voxelwise SRTM2s, both using either the brainstem or the cerebellum; and voxelwise SA. However, the SRTMs using the brainstem yielded a lower median BS-CV (7% for regional, 7% voxelwise) than the other variants (8-11%), resulting in lower ICCs. The median ICCs across six regions were 0.89 (interquartile range 0.75-0.90) for voxelwise SA, 0.71 (0.64-0.84) for regional SRTM-cerebellum and 0.83 (0.70-0.86) for voxelwise SRTM-cerebellum. The ICCs for the hippocampus were 0.89 for voxelwise SA, 0.95 for regional SRTM-cerebellum and 0.93 for voxelwise SRTM-cerebellum.
Quantification of
CRo15-4513 binding shows very good to excellent reproducibility with SRTM and with voxelwise SA which, however, requires an arterial ppIF. Quantification in the α5 subunit-rich hippocampus is particularly reliable. The very low expression of the α5 in the cerebellum (Fritschy and Mohler, 1995; Veronese et al., 2016) and the substantial α1 subunit density in this region may hamper the application of reference tissue methods.
Endocannabinoids are involved in normal cognition, and dysfunction in cannabinoid-receptor-mediated neurotransmission has been suggested in a variety of neurological and psychiatric pathologies. The ...type 1 cannabinoid receptor (CB1) is widely expressed in the human central nervous system. The objective of this study was to quantify the test–retest reproducibility of measures of the PET ligand 11CMePPEP in order to assess the stability of CB1-receptor quantification in humans in vivo.
Fifteen healthy subjects (eight females; median age 32years, range 25 to 65years) had a 90-minute PET scan on two occasions after injection of a median dose of 11CMePPEP of 364MBq. Metabolite-corrected arterial plasma input functions were obtained for all scans. Eight ROIs, reflecting different levels of receptor densities/concentrations, were defined automatically: hippocampus, anterior cingulate gyrus, inferior frontal gyrus, caudate nucleus, globus pallidus, nucleus accumbens, thalamus, and pons. We used seven quantification methods: reversible compartmental models with one and two tissue classes, two and four rate constants, and a variable blood volume term (2kbv; 4kbv); model-free (spectral) analyses with and without regularisation, including one with voxel-wise quantification; the simplified reference tissue model (SRTM) with pons as a pseudo-reference region; and modified standard uptake values (mSUVs) calculated for the period of ~30–60min after injection. Percentage test–retest change and between-subject variability were both assessed, and test–retest reliability was quantified by the intraclass correlation coefficient (ICC). The ratio of binding estimates pallidum:pons served as an indicator of a method's ability to reflect binding heterogeneity.
Neither the SRTM nor the 4kbv model produced reliable measures, with ICCs around zero. Very good (>0.75) or excellent (>0.80) ICCs were obtained with the other methods. The most reliable were spectral analysis parametric maps (average across regions±standard deviation 0.83±0.03), rank shaping regularised spectral analysis (0.82±0.05), and the 2kbv model (0.82±0.09), but mSUVs were also reliable for most regions (0.79±0.13). Mean test–retest changes among the five well-performing methods ranged from 12±10% for mSUVs to 16% for 2kbv. Intersubject variability was high, with mean between-subject coefficients of variation ranging from 32±13% for mSUVs to 45% for 2kbv. The highest pallidum:pons ratios of binding estimates were achieved by mSUV (4.2), spectral analysis-derived parametric maps (3.6), and 2kbv (3.6).
Quantification of CB1 receptor availability using 11CMePPEP shows good to excellent reproducibility with several kinetic models and model-free analyses, whether applied on a region-of-interest or voxelwise basis. Simple mSUV measures were also reliable for most regions, but do not allow fully quantitative interpretation. 11CMePPEP PET is well placed as a tool to investigate CB1-receptor mediated neurotransmission in health and disease.
Cannabinoid receptor concentrations assessed with 11CMePPEP-PET. Top, reliability (ICCs±SDs) of different quantification strategies: blue, compartmental models; red, spectral analysis variants; green, SRTM; yellow, modified SUVs. Bottom, parametric VT map. Display omitted
•11CMePPEP is a PET tracer for cannabinoid receptors (CB1R).•Extensive evaluation of 11CMePPEP data quantification strategies in large sample•We highlight successful methods to quantify CB1R in regions of interest.•Highly reliable parametric maps (ICC 0.83±0.03) allow whole-brain surveys.•Modified standard uptake values also reliable, without arterial input functions
Introduction Alteration of γ-aminobutyric acid “A” (GABAA) receptor-mediated neurotransmission has been associated with various neurological and psychiatric disorders. 11CRo15-4513 is a PET ligand ...with high affinity for α5-subunit-containing GABAAreceptors, which are highly expressed in limbic regions of the human brain (Sur et al., 1998). We quantified the test-retest reproducibility of measures of 11CRo15-4513 binding derived from six different quantification methods (12 variants). Methods Five healthy males (median age 40 years, range 38-49 years) had a 90-min PET scan on two occasions (median interval 12 days, range 11-30 days), after injection of a median dose of 441 MegaBequerels of 11CRo15-4513. Metabolite-corrected arterial plasma input functions (parent plasma input functions, ppIFs) were generated for all scans. We quantified regional binding using six methods (12 variants), some of which were region-based (applied to the average time-activity curve within a region) and others were voxel-based: 1) Models requiring arterial ppIFs - regional reversible compartmental models with one and two tissue compartments (2kbv and 4kbv); 2) Regional and voxelwise Logan’s graphical analyses (Logan et al., 1990), which required arterial ppIFs; 3) Model-free regional and voxelwise (exponential) spectral analyses (SA; (Cunningham and Jones, 1993)), which also required arterial ppIFs; 4) methods not requiring arterial ppIFs - voxelwise standardised uptake values (Kenney et al., 1941), and regional and voxelwise simplified reference tissue models (SRTM/SRTM2) using brainstem or alternatively cerebellum as pseudo-reference regions (Lammertsma and Hume, 1996; Gunn et al., 1997). To compare the variants, we sampled the mean values of the outcome parameters within six bilateral, non-reference grey matter regions-of-interest. Reliability was quantified in terms of median absolute percentage test-retest differences (MA-TDs; preferentially low) and between-subject coefficient of variation (BS-CV, preferentially high), both compounded by the intraclass correlation coefficient (ICC). These measures were compared between variants, with particular interest in the hippocampus. Results Two of the six methods (5/12 variants) yielded reproducible data (i.e. MA-TD <10%): regional SRTMs and voxelwise SRTM2s, both using either the brainstem or the cerebellum; and voxelwise SA. However, the SRTMs using the brainstem yielded a lower median BS-CV (7% for regional, 7% voxelwise) than the other variants (8-11%), resulting in lower ICCs. The median ICCs across six regions were 0.89 (interquartile range 0.75-0.90) for voxelwise SA, 0.71 (0.64-0.84) for regional SRTM-cerebellum and 0.83 (0.70-0.86) for voxelwise SRTM-cerebellum. The ICCs for the hippocampus were 0.89 for voxelwise SA, 0.95 for regional SRTM-cerebellum and 0.93 for voxelwise SRTM-cerebellum. Conclusion Quantification of 11CRo15-4513 binding shows very good to excellent reproducibility with SRTM and with voxelwise SA which, however, requires an arterial ppIF. Quantification in the α5 subunit-rich hippocampus is particularly reliable. The very low expression of the α5 in the cerebellum (Fritschy and Mohler, 1995; Veronese et al., 2016) and the substantial α1 subunit density in this region may hamper the application of reference tissue methods.
Introduction
The NMDA receptor radiotracer
18
FGE-179 has been used with 90-min scans and arterial plasma input functions. We explored whether (1) arterial blood sampling is avoidable and (2) ...shorter scans are feasible.
Methods
For 20 existing
18
FGE-179 datasets, we generated (1) standardised uptake values (SUVs) over eight intervals; (2) volume of distribution (
V
T
) images using population-based input functions (PBIFs), scaled using one parent plasma sample; and (3)
V
T
images using three shortened datasets, using the original parent plasma input functions (ppIFs).
Results
Correlations with the original ppIF-derived 90-min
V
T
s increased for later interval SUVs (maximal
ρ
= 0.78; 80–90 min). They were strong for PBIF-derived
V
T
s (
ρ
= 0.90), but between-subject coefficient of variation increased. Correlations were very strong for the 60/70/80-min original ppIF-derived
V
T
s (
ρ
= 0.97–1.00), which suffered regionally variant negative bias.
Conclusions
Where arterial blood sampling is available, reduction of scan duration to 60 min is feasible, but with negative bias. The performance of SUVs was more consistent across participants than PBIF-derived
V
T
s.
Alteration of γ-aminobutyric acid “A” (GABAA) receptor-mediated neurotransmission has been associated with various neurological and psychiatric disorders. 11CRo15-4513 is a PET ligand with high ...affinity for α5-subunit-containing GABAA receptors, which are highly expressed in limbic regions of the human brain (Sur et al., 1998). We quantified the test-retest reproducibility of measures of 11CRo15-4513 binding derived from six different quantification methods (12 variants).
Five healthy males (median age 40 years, range 38–49 years) had a 90-min PET scan on two occasions (median interval 12 days, range 11–30 days), after injection of a median dose of 441 MegaBequerels of 11CRo15-4513. Metabolite-corrected arterial plasma input functions (parent plasma input functions, ppIFs) were generated for all scans.
We quantified regional binding using six methods (12 variants), some of which were region-based (applied to the average time-activity curve within a region) and others were voxel-based: 1) Models requiring arterial ppIFs – regional reversible compartmental models with one and two tissue compartments (2kbv and 4kbv); 2) Regional and voxelwise Logan’s graphical analyses (Logan et al., 1990), which required arterial ppIFs; 3) Model-free regional and voxelwise (exponential) spectral analyses (SA; (Cunningham and Jones, 1993)), which also required arterial ppIFs; 4) methods not requiring arterial ppIFs – voxelwise standardised uptake values (Kenney et al., 1941), and regional and voxelwise simplified reference tissue models (SRTM/SRTM2) using brainstem or alternatively cerebellum as pseudo-reference regions (Lammertsma and Hume, 1996; Gunn et al., 1997).
To compare the variants, we sampled the mean values of the outcome parameters within six bilateral, non-reference grey matter regions-of-interest. Reliability was quantified in terms of median absolute percentage test-retest differences (MA-TDs; preferentially low) and between-subject coefficient of variation (BS-CV, preferentially high), both compounded by the intraclass correlation coefficient (ICC). These measures were compared between variants, with particular interest in the hippocampus.
Two of the six methods (5/12 variants) yielded reproducible data (i.e. MA-TD <10%): regional SRTMs and voxelwise SRTM2s, both using either the brainstem or the cerebellum; and voxelwise SA. However, the SRTMs using the brainstem yielded a lower median BS-CV (7% for regional, 7% voxelwise) than the other variants (8–11%), resulting in lower ICCs. The median ICCs across six regions were 0.89 (interquartile range 0.75–0.90) for voxelwise SA, 0.71 (0.64–0.84) for regional SRTM-cerebellum and 0.83 (0.70–0.86) for voxelwise SRTM-cerebellum. The ICCs for the hippocampus were 0.89 for voxelwise SA, 0.95 for regional SRTM-cerebellum and 0.93 for voxelwise SRTM-cerebellum.
Quantification of 11CRo15-4513 binding shows very good to excellent reproducibility with SRTM and with voxelwise SA which, however, requires an arterial ppIF. Quantification in the α5 subunit-rich hippocampus is particularly reliable. The very low expression of the α5 in the cerebellum (Fritschy and Mohler, 1995; Veronese et al., 2016) and the substantial α1 subunit density in this region may hamper the application of reference tissue methods.
Introduction:
Cannabis-based medicinal products (CBMPs) have been identified as a promising novel therapeutic for symptoms and comorbidities related to autism spectrum disorder (ASD). However, there ...is a paucity of clinical evidence of their efficacy and safety. Objective: This case series aims to assess changes to health-related quality of life and the incidence of adverse events in patients treated with CBMPs for associated symptoms of ASD enrolled on the UK Medical Cannabis Registry (UKMCR).
Methods:
Patients treated with CBMPs for ASD-related symptoms for a minimum of 1 month were identified from the UKMCR. Primary outcomes were changes in validated patient-reported outcome measures Generalised Anxiety Disorder-7 (GAD-7), Single-Item Sleep Quality Scale (SQS), 5-level version of the EQ-5D (EQ-5D-5L) index values at 1, 3 and 6 months compared with baseline. Adverse events were recorded and analysed. Statistical significance was determined by p < 0.050.
Results:
Seventy-four patients with ASD were included in the analysis. The mean age of participants was 32.7 (±11.6) years. There were significant improvements in general health-related quality of life and sleep as assessed by the EQ-5D-5L, SQS and GAD-7 at 1 and 3 months, with sustained changes in EQ-5D-5L and SQS at 6 months (p < 0.010). There were 180 (243.2%) adverse events reported by 14 (18.9%) participants. If present, adverse events were commonly mild (n = 58; 78.4%) or moderate (n = 81; 109.5%), rather than severe (n = 41; 55.4%).
Conclusion:
This study demonstrated an associated improvement in general health-related quality of life, and anxiety- and sleep-specific symptoms following initiation of treatment with CBMPs in patients with ASD. These findings, while promising, are limited by the confines of the study which lacks a control arm and is subject to attrition bias. Therefore, further evaluation is required with randomised controlled trials.
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