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EJNMMI Research
Published in: EJNMMI Research 1/2018

Open Access 01-12-2018 | Original research

Test-retest reliability and convergent validity of (R)-[11C]PK11195 outcome measures without arterial input function

Authors: Pontus Plavén-Sigray, Granville James Matheson, Zsolt Cselényi, Aurelija Jucaite, Lars Farde, Simon Cervenka

Published in: EJNMMI Research | Issue 1/2018

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Abstract

Purpose

The PET radioligand (R)-[11C]PK11195 is used to quantify the 18-kDa translocator protein (TSPO), a marker for glial activation. Since there is no brain region devoid of TSPO, an arterial input function (AIF) is ideally required for quantification of binding. However, obtaining an AIF is experimentally demanding, is sometimes uncomfortable for participants, and can introduce additional measurement error during quantification. The objective of this study was to perform an evaluation of the test-retest reliability and convergent validity of techniques used for quantifying (R)-[11C]PK11195 binding without an AIF in clinical studies.

Methods

Data from six healthy individuals who participated in two PET examinations, 6 weeks apart, were analyzed. Regional non-displaceable binding potential (BPND) values were calculated using the simplified reference tissue model, with either cerebellum as reference region or a reference input derived using supervised cluster analysis (SVCA). Standardized uptake values (SUVs) were estimated for the time interval of 40–60 min.

Results

Test-retest reliability for BPND estimates were poor (80% of ICCs < 0.5). BPND estimates derived without an AIF were not correlated with BPND, total or specific distribution volume from the 2TCM using an AIF (all R2 < 12%). SUVs showed moderate reliability but no correlation to any other outcome measure.

Conclusions

Caution is warranted when interpreting patient-control comparisons employing (R)-[11C]PK11195 outcome measures obtained without an AIF.
Appendix
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Literature
1.
Venneti S, Lopresti BJ, Wiley CA. Molecular imaging of microglia/macrophages in the brain. Glia. 2013;61:10–23 Wiley Online Library.CrossRef
2.
Politis M, Su P, Piccini P. Imaging of microglia in patients with neurodegenerative disorders. Front Pharmacol. 2012;3:96 Frontiers Media SA.CrossRef
3.
Innis RB, Cunningham VJ, Delforge J, Fujita M, Gjedde A, Gunn RN, et al. Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab. 2007;27:1533–9.CrossRef
4.
Van Der Laken CJ, Elzinga EH, Kropholler MA, Molthoff CFM, van der Heijden JW, Maruyama K, et al. Noninvasive imaging of macrophages in rheumatoid synovitis using 11C-(R)-PK11195 and positron emission tomography. Arthritis Rheumatol. 2008;58:3350–5 Wiley Online Library.CrossRef
5.
Kropholler MA, Boellaard R, Elzinga EH, Van der Laken CJ, Maruyama K, Kloet RW, et al. Quantification of (R)-[11 C] PK11195 binding in rheumatoid arthritis. Eur J Nucl Med Mol Imaging. 2009;36:624–31 Springer.CrossRef
6.
Schuitemaker A, Van Berckel BNM, Kropholler MA, Kloet RW, Jonker C, Scheltens P, et al. Evaluation of methods for generating parametric (R)-[11C] PK11195 binding images. J Cereb Blood Flow Metab. 2007;27:1603–15 SAGE publications Sage UK: London, England.CrossRef
7.
Imaizumi M, Briard E, Zoghbi SS, Gourley JP, Hong J, Musachio JL, et al. Kinetic evaluation in nonhuman primates of two new PET ligands for peripheral benzodiazepine receptors in brain. Synapse. 2007;61:595–605 Wiley Online Library.CrossRef
8.
Turkheimer FE, Edison P, Pavese N, Roncaroli F, Anderson AN, Hammers A, et al. Reference and target region modeling of [11C]-(R)-PK11195 brain studies. J Nucl Med Soc Nuclear Med. 2007;48:158–67.
9.
Yaqub M, Van Berckel BN, Schuitemaker A, Hinz R, Turkheimer FE, Tomasi G, et al. Optimization of supervised cluster analysis for extracting reference tissue input curves in (R)-[11C] PK11195 brain PET studies. J Cereb Blood Flow Metab. 2012;32:1600–8 SAGE Publications Sage UK: London, England.CrossRef
10.
Lammertsma AA, Hume SP. Simplified reference tissue model for PET receptor studies. NeuroImage. 1996;4:153–8.CrossRef
11.
Van Berckel BN, Bossong MG, Boellaard R, Kloet R, Schuitemaker A, Caspers E, et al. Microglia activation in recent-onset schizophrenia: a quantitative (R)-[11 C] PK11195 positron emission tomography study. Biol Psychiatry. 2008;64:820–2 Elsevier.CrossRef
12.
13.
Rissanen E, Tuisku J, Rokka J, Paavilainen T, Parkkola R, Rinne JO, et al. In vivo detection of diffuse inflammation in secondary progressive multiple sclerosis using PET imaging and the radioligand 11C-PK11195. J Nucl Med. Soc Nuclear Med. 2014;55:939–44.CrossRef
14.
Folkersma H, Boellaard R, Yaqub M, Kloet RW, Windhorst AD, Lammertsma AA, et al. Widespread and prolonged increase in (R)-11C-PK11195 binding after traumatic brain injury. J Nucl Med. Soc Nuclear Med. 2011;52:1235–9.CrossRef
15.
Van Der Doef TF, De Witte LD, Sutterland AL, Jobse E, Yaqub M, Boellaard R, et al. In vivo (R)-[11C]PK11195 PET imaging of 18kDa translocator protein in recent onset psychosis. NPJ Schizophr. 2016;2:16031 Nature Publishing Group.CrossRef
16.
Schuitemaker A, van der Doef TF, Boellaard R, van der Flier WM, Yaqub M, Windhorst AD, et al. Microglial activation in healthy aging. Neurobiol Aging. 2012;33:1067–72 Elsevier.CrossRef
17.
Kumar A, Muzik O, Shandal V, Chugani D, Chakraborty P, Chugani HT. Evaluation of age-related changes in translocator protein (TSPO) in human brain using 11 C-[R]-PK11195 PET. J Neuroinflammation. 2012;9:232 BioMed Central.CrossRef
18.
Doble A, Malgouris C, Daniel M, Daniel N, Imbault F, Basbaum A, et al. Labelling of peripheral-type benzodiazepine binding sites in human brain with [3H] PK 11195: anatomical and subcellular distribution. Brain Res Bull. 1987;18:49–61 Elsevier.CrossRef
19.
Kropholler MA, Boellaard R, Schuitemaker A, Folkersma H, van Berckel BNM, Lammertsma AA. Evaluation of reference tissue models for the analysis of [11C](R)-PK11195 studies. J Cereb Blood Flow Metab. 2006;26:1431–41 SAGE publications Sage UK: London, England.CrossRef
20.
Holmes SE, Hinz R, Drake RJ, Gregory CJ, Conen S, Matthews JC, et al. In vivo imaging of brain microglial activity in antipsychotic-free and medicated schizophrenia: a [11C](R)-PK11195 positron emission tomography study. Mol Psychiatry. 2016;21:1672–9 Nature Publishing Group.CrossRef
21.
Di Biase MA, Zalesky A, O’keefe G, Laskaris L, Baune BT, Weickert CS, et al. PET imaging of putative microglial activation in individuals at ultra-high risk for psychosis, recently diagnosed and chronically ill with schizophrenia. Transl Psychiatry. 2017;7:e1225 Nature Publishing Group.CrossRef
22.
Holmes SE, Hinz R, Conen S, Gregory CJ, Matthews JC, Anton-Rodriguez JM, et al. Elevated translocator protein in anterior cingulate in major depression and a role for inflammation in suicidal thinking: a positron emission tomography study. Biol Psychiatry. 2018;83:61–9 Elsevier.CrossRef
23.
Su Z, Herholz K, Gerhard A, Roncaroli F, Du Plessis D, Jackson A, et al. [11C]-(R) PK11195 tracer kinetics in the brain of glioma patients and a comparison of two referencing approaches. Eur J Nucl Med Mol Imaging. 2013;40:1406–19 Springer.CrossRef
24.
Kropholler MA, Boellaard R, Schuitemaker A, van Berckel BNM, Luurtsema G, Windhorst AD, et al. Development of a tracer kinetic plasma input model for (R)-[11C] PK11195 brain studies. J Cereb Blood Flow Metab. 2005;25:842–51 SAGE publications Sage UK: London, England.CrossRef
25.
Jučaite A, Cselényi Z, Arvidsson A, Ahlberg G, Julin P, Varnäs K, et al. Kinetic analysis and test-retest variability of the radioligand [11C](R)-PK11195 binding to TSPO in the human brain - a PET study in control subjects. EJNMMI Res. 2012;2:15.CrossRef
26.
Boellaard R, Turkheimer FE, Hinz R, Schuitemaker A, Scheltens P, van Berckel BNM, et al. Performance of a modified supervised cluster algorithm for extracting reference region input functions from (R)-[11 C] PK11195 brain PET studies. Nucl Sci Symp Conf Rec 2008 NSS’08 IEEE. 2008:5400–2 IEEE. https://​doi.​org/​10.​1109/​NSSMIC.​2008.​4774453.
27.
Tomasi G, Edison P, Bertoldo A, Roncaroli F, Singh P, Gerhard A, et al. Novel reference region model reveals increased microglial and reduced vascular binding of 11C-(R)-PK11195 in patients with Alzheimer’s disease. J Nucl Med. 2008;49:1249–56.CrossRef
28.
Weir JP. Quantifying test-retest reliability using the intraclass correlation coefficient and the SEM. J Strength Cond Res. 2005;19:231–40 LWW.PubMed
29.
30.
Farde L. TSPO binding may also represent ‘resting’microglia. Clin Transl Imaging. 2015;3:491–2 Springer.CrossRef
31.
Portney LG, Watkins MP. Foundations of clinical research: application to practice. 3rd ed. Stamford: Lange; 2009.
32.
Schuirmann DJ. A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability. J Pharmacokinet Pharmacodyn. 1987;15:657–80 Springer.CrossRef
33.
34.
Dienes Z. Using Bayes to get the most out of non-significant results. Front Psychol. 2014;5:781 Frontiers.CrossRef
35.
36.
Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015;14:388–405 Elsevier.CrossRef
37.
Fujita M, Kobayashi M, Ikawa M, Gunn RN, Rabiner EA, Owen DR, et al. Comparison of four 11C-labeled PET ligands to quantify translocator protein 18 kDa (TSPO) in human brain: (R)-PK11195, PBR28, DPA-713, and ER176—based on recent publications that measured specific-to-non-displaceable ratios. EJNMMI Res. 2017;7:84 Available from: https://​doi.​org/​10.​1186/​s13550-017-0334-8.CrossRef
38.
Collste K, Forsberg A, Varrone A, Amini N, Aeinehband S, Yakushev I, et al. Test–retest reproducibility of [11C] PBR28 binding to TSPO in healthy control subjects. Eur J Nucl Med Mol Imaging. 2016;43:173–83 Springer.CrossRef
39.
Kreisl WC, Mbeo G, Fujita M, Zoghbi SS, Pike VW, Innis RB, et al. Stroke incidentally identified using improved positron emission tomography for microglial activation. Arch Neurol. 2009;66:1288–9 American Medical Association.CrossRef
Metadata
Title
Test-retest reliability and convergent validity of (R)-[11C]PK11195 outcome measures without arterial input function
Authors
Pontus Plavén-Sigray
Granville James Matheson
Zsolt Cselényi
Aurelija Jucaite
Lars Farde
Simon Cervenka
Publication date
01-12-2018
Publisher
Springer Berlin Heidelberg
Published in
EJNMMI Research / Issue 1/2018
Electronic ISSN: 2191-219X
DOI
https://doi.org/10.1186/s13550-018-0455-8

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