Test–retest reproducibility of cannabinoid-receptor type 1 availability quantified with the PET ligand [11C]MePPEP

• Published in: NeuroImage (Orlando, Fla.) Vol. 97; pp. 151 - 162
• Main Authors: Riaño Barros, Daniela A., McGinnity, Colm J., Rosso, Lula, Heckemann, Rolf A., Howes, Oliver D., Brooks, David J., Duncan, John S., Turkheimer, Federico E., Koepp, Matthias J., Hammers, Alexander
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 15.08.2014; Elsevier; Elsevier Limited; Academic Press
• Subjects: Adult; Aged; Algorithms; Bioengineering; Biological and medical sciences; Blood Volume; Brain; Brain - diagnostic imaging; CB1; Cognitive science; Consent; Female; Fundamental and applied biological sciences. Psychology; Humans; Imaging; Intra-class correlation coefficient; Life Sciences; Magnetic Resonance Imaging; Male; Medical sciences; Methods; Middle Aged; Neuropharmacology; Neuroscience; Pharmacology. Drug treatments; Positron Emission Tomography; Positron-Emission Tomography - methods; Psychodysleptics: hallucinogen; Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Pyrrolidinones; Radiopharmaceuticals; Receptor, Cannabinoid, CB1 - metabolism; Reliability; Reproducibility of Results; Standard deviation; Urine; Vertebrates: nervous system and sense organs; Web hosting; CB1; Intra-class correlation coefficient; Reliability; Positron Emission Tomography; Cannabinoid receptor; Emission tomography; CB
• ISSN: 1053-8119; 1095-9572
• DOI: 10.1016/j.neuroimage.2014.04.020

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 [11C]MePPEP 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 [11C]MePPEP 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 [11C]MePPEP 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. [11C]MePPEP PET is well placed as a tool to investigate CB1-receptor mediated neurotransmission in health and disease. Cannabinoid receptor concentrations assessed with [11C]MePPEP-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] •[11C]MePPEP is a PET tracer for cannabinoid receptors (CB1R).•Extensive evaluation of [11C]MePPEP 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