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

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 object...

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Published inNeuroImage (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
LanguageEnglish
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
Online AccessGet full text

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Abstract 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
AbstractList 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
Cannabinoid receptor concentrations assessed with [ 11 C]MePPEP-PET. Top, reliability (ICCs ± SDs) of different quantification strategies: blue, compartmental models; red, spectral analysis variants; green, SRTM; yellow, modified SUVs. Bottom, parametric V T map. • [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
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 [(11)C]MePPEP in order to assess the stability of CB1-receptor quantification in humans in vivo. Fifteen healthy subjects (eight females; median age 32 years, range 25 to 65 years) had a 90-minute PET scan on two occasions after injection of a median dose of [(11)C]MePPEP of 364 MBq. 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 ~30-60 min 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 [(11)C]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. [(11)C]MePPEP PET is well placed as a tool to investigate CB1-receptor mediated neurotransmission in health and disease.
BackgroundEndocannabinoids 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.MethodsFifteen healthy subjects (eight females; median age 32 years, range 25 to 65 years) had a 90-minute PET scan on two occasions after injection of a median dose of [11C]MePPEP of 364 MBq. 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 ~ 30–60 min 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.ResultsNeither 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).ConclusionQuantification 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.
Background 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. Methods 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. Results 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). Conclusion Quantification of CB1receptor 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.
Background 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. Methods 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. Results 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 plus or minus standard deviation 0.83 plus or minus 0.03), rank shaping regularised spectral analysis (0.82 plus or minus 0.05), and the 2kbv model (0.82 plus or minus 0.09), but mSUVs were also reliable for most regions (0.79 plus or minus 0.13). Mean test-retest changes among the five well-performing methods ranged from 12 plus or minus 10% for mSUVs to 16% for 2kbv. Intersubject variability was high, with mean between-subject coefficients of variation ranging from 32 plus or minus 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). Conclusion 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.
Author Riaño Barros, Daniela A.
Hammers, Alexander
Koepp, Matthias J.
Heckemann, Rolf A.
McGinnity, Colm J.
Howes, Oliver D.
Rosso, Lula
Turkheimer, Federico E.
Brooks, David J.
Duncan, John S.
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  givenname: Daniela A.
  surname: Riaño Barros
  fullname: Riaño Barros, Daniela A.
  organization: Centre for Neuroscience, Department of Medicine, Imperial College London, London, UK
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  givenname: Colm J.
  orcidid: 0000-0002-2692-918X
  surname: McGinnity
  fullname: McGinnity, Colm J.
  organization: Centre for Neuroscience, Department of Medicine, Imperial College London, London, UK
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  givenname: Lula
  surname: Rosso
  fullname: Rosso, Lula
  organization: Centre for Neuroscience, Department of Medicine, Imperial College London, London, UK
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  surname: Heckemann
  fullname: Heckemann, Rolf A.
  organization: Centre for Neuroscience, Department of Medicine, Imperial College London, London, UK
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  givenname: Oliver D.
  surname: Howes
  fullname: Howes, Oliver D.
  organization: Centre for Neuroscience, Department of Medicine, Imperial College London, London, UK
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  surname: Brooks
  fullname: Brooks, David J.
  organization: Centre for Neuroscience, Department of Medicine, Imperial College London, London, UK
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  givenname: John S.
  orcidid: 0000-0002-1373-0681
  surname: Duncan
  fullname: Duncan, John S.
  organization: Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, UK
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  givenname: Federico E.
  orcidid: 0000-0002-3766-3815
  surname: Turkheimer
  fullname: Turkheimer, Federico E.
  organization: Centre for Neuroimaging, Institute of Psychiatry, King's College London, London, UK
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  givenname: Matthias J.
  surname: Koepp
  fullname: Koepp, Matthias J.
  organization: Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, UK
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  givenname: Alexander
  surname: Hammers
  fullname: Hammers, Alexander
  email: alexander.hammers@fondation-neurodis.org
  organization: Centre for Neuroscience, Department of Medicine, Imperial College London, London, UK
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ContentType Journal Article
Copyright 2014
2015 INIST-CNRS
Crown Copyright © 2014. Published by Elsevier Inc. All rights reserved.
Copyright Elsevier Limited Aug 15, 2014
Distributed under a Creative Commons Attribution 4.0 International License
Crown Copyright © 2014 Published by Elsevier Inc. All rights reserved. 2014
Copyright_xml – notice: 2014
– notice: 2015 INIST-CNRS
– notice: Crown Copyright © 2014. Published by Elsevier Inc. All rights reserved.
– notice: Copyright Elsevier Limited Aug 15, 2014
– notice: Distributed under a Creative Commons Attribution 4.0 International License
– notice: Crown Copyright © 2014 Published by Elsevier Inc. All rights reserved. 2014
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Keywords CB1
Intra-class correlation coefficient
Reliability
Positron Emission Tomography
Cannabinoid receptor
Emission tomography
CB
Language English
License http://creativecommons.org/licenses/by/3.0
CC BY 4.0
Crown Copyright © 2014. Published by Elsevier Inc. All rights reserved.
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Snippet Endocannabinoids are involved in normal cognition, and dysfunction in cannabinoid-receptor-mediated neurotransmission has been suggested in a variety of...
Background Endocannabinoids are involved in normal cognition, and dysfunction in cannabinoid-receptor-mediated neurotransmission has been suggested in a...
BackgroundEndocannabinoids are involved in normal cognition, and dysfunction in cannabinoid-receptor-mediated neurotransmission has been suggested in a variety...
Cannabinoid receptor concentrations assessed with [ 11 C]MePPEP-PET. Top, reliability (ICCs ± SDs) of different quantification strategies: blue, compartmental...
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SubjectTerms 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
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Title Test–retest reproducibility of cannabinoid-receptor type 1 availability quantified with the PET ligand [11C]MePPEP
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