Quantification of [11C]-R-PK11195 brain PET studies
PK11195 is a selective ligand for the translocator protein (TSPO), formerly known as peripheral benzodiazepine receptor (PBR).
Analysis methods used in literature
Schuitemaker et al. (2007a) published an extensive comparison of methods for producing parametric images of [11C]-R-PK11195 binding. They suggest that when plasma input is available the Logan graphical analysis should be used (30-60 min linear fit), and with reference region input RPM1 (original version by Gunn et al. 1997) should be used, provided that the range of basis functions is carefully optimized.
2-tissue compartment model with plasma input
Kropholler et al. (2004) have validated the use of 2-tissue compartment model in estimating the total distribution volume and binding potential (k3/k4). Vb was fitted, but K1/k2 was fixed to whole cortex value. With another tracer for peripheral benzodiazepine receptor ([11C]DAA1106) K1/k2 was found to differ among individuals (Ikoma et al., 2007), suggesting that k3/k4 should be preferred over DV.
Reference tissue input
Because glial cells are located everywhere in the brain, there is no true reference region for [11C]-R-PK11195 binding. Therefore, cluster analysis has been applied in extracting a reference tissue curve from the dynamic image, and it is used as input for the simplified reference tissue model (Banati et al., 2000; Kropholler et al., 2006 and 2007).
However, the unsupervised tissue classification does not succeed in finding a reference tissue curve in all cases, and therefore a supervised clustering algorithm has been developed and validated (Turkheimer et al. 2007), and Matlab software Super-PK is available for this purpose. Reference region curve was then used to estimate binding potential (BPND) with simplified reference tissue model (SRTM) and rank-shaping regularized exponential spectral analysis (RS-ESA). Wavelet-based Logan plot, basis pursuit and SRTM give better ICC than ratio or traditional Logan method (Anderson et al., 2007).
For certain diseases it has been shown that cerebellum or certain cortical regions do not have increased microglial burden, and then these regions can be used as reference region for reference tissue model (Gerhard et al., 2002; 2005).
Ratio method with white matter as reference tissue
Hammoud et al. (2005) validated by simulations the calculation of tissue-to-white matter ratio as a parameter related to binding potential. They calculated the ratio from 10 to 60 min from the injection. Unfortunately this method was not included in the comparison by Schuitemaker et al. (2007).
Suggested analysis method for Turku
[11C]-R-PK11195 has radioactive metabolites in the plasma and at least [11C]CH2O (formaldehyde) easily penetrates the blood-brain barrier (De Vos et al., 1999). The uptake of labeled metabolites in the brain precludes perfect quantification of peripheral benzodiazepine receptors, but an index related to the receptor concentration can still be achieved.
When plasma curves corrected for radioactive metabolites are available the method of Kropholler et al. (2004) is preferrable choice for analysis method for regional data. To calculate parametric volume of distribution (VT) images the Logan graphical analysis is recommended (Schuitemaker et al., 2007), although a strictly linear phase can not be achieved.
When plasma curves are not available, the very simple method by Hammoud et al. (2005) seems like worth testing. Ratio image can be calculated e.g. using program imgratio. However, if precise quantitation is needed and extraction of valid reference tissue curves is possible (supervised cluster analysis is available in TPC; contact Jouni Tuisku), then RPM1 method is recommended (Schuitemaker et al., 2012), using imgbfbp in TPC. Currently, the range of basis functions is not yet determined for use with [11C]-R-PK11195 in TPC.
Processing of plasma data in TPC
A script called
PK11195_input.bat is available for corrections of plasma and blood data.
As input it needs four data files, and haematocrit for plasma-blood TAC conversion:
- Blood file from the online sampler (*.bld, *.alg, *.lis, *.txt),
- manual plasma sample file (*ap.kbq)
- count-rate file (*.cr, *.r, *.hc, *.head or *.dft),
- fraction file of parent tracer in plasma (*.rat)
- Haematocrit (e.g. 0.40)
In addition, user has to give the names of output files:
- Parent tracer TAC in plasma (*apc.kbq),
- Metabolite TAC in plasma (*apm.kbq),
- Blood TAC (*ab.kbq).
Output TACs are calibrated and corrected (for physical decay, and delay-time). In addition, the script will create SVG and/or PNG images where the user can verify how fit of an exponential function into the fraction data succeeded, how delay correction succeeded and how the result curves look like.
Dispersion correction is not applied because the effect of dispersion is minimal in case of an 11C labeled tracer.
Script can be used in Windows command-prompt window directly, or a batch file (script) can be written that processes all studies.
The parent plasma curve that you will receive from the script can then be used as such for the graphical analysis.
Anderson AN, Pavese N, Edison P, Tai YF, Hammers A, Gerhard A, Brooks DJ, Turkheimer FE. A systematic comparison of kinetic modelling methods generating parametric maps for [11C]-(R)-PK11195. Neuroimage 2007; 36: 28-37.
Banati RB, Newcombe J, Gunn RN, Cagnin A, Turkheimer F, Heppner F, Price G, Wegner F, Giovannoni G, Miller DH, Perkin GD, Smith T, Hewson AK, Bydder G, Kreutzberg GW, Jones T, Cuzner ML, Myers R. The peripheral benzodiazepine binding site in the brain in multiple sclerosis. Quantitative in vivo imaging of microglia as a measure of disease activity. Brain 2000; 123:2321-2337.
Banati RB. Visualising microglial activation in vivo. Glia 2002; 40(2): 206-217.
De Vos F, Dumont F, Santens P, Slegers G, Dierckx R, De Reuck J. High-performance liquid chromatographic determination of [11C]1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide in mouse plasma and tissue and in human plasma. J. Chromatogr. B 1999; 736: 61-66.
Gerhard A, Schwarz J, Myers R, Wise R, Banati RB. Evolution of microglial activation in patients after ischemic stroke: a [11C](R)-PK11195 PET study. Neuroimage 2005; 24: 591-595.
Gerhard A, Watts J, Trender-Gerhard I, Turkheimer F, Banati RB, Bhatia K, Brooks DJ. In vivo imaging of microglial activation with [11C](R)-PK11195 PET in corticobasal degeneration. Mov Disord. 2004; 19(10): 1221-1226.
Hammoud DA, Endres CJ, Chander AR, Guilarte TR, Wong DF, Sacktor NC, McArthur JC, Pomper MG. Imaging glial cell activation with [11C]-R-PK11195 in patients with AIDS. J. Neurovirol. 2005; 11(4): 346-355.
Ikoma Y, Yasuno F, Ito H, Suhara T, Ota M, Toyama H, Fujimura Y, Takano A, Maeda J, Zhang M-R, Nakao R, Suzuki K. Quantitative analysis for estimating binding potential of the peripheral benzodiazepine receptor with [11C]DAA1106. J. Cereb. Blood Flow Metab. 2007; 27: 173-184.
Kropholler MA, Boellaard R, Schuitemaker A, van Berckel BNM, Luurtsema G, Windhorst AD, Lammertsma AA. Development of a tracer kinetic plasma input model for (R)-[11C]PK11195 brain studies. J. Cereb. Blood Flow Metab. 2005; 25(7): 842-851.
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(11): 1431-1441.
Kropholler MA, Boellaard R, van Berckel BN, Schuitemaker A, Kloet RW, Lubberink MJ, Jonker C, Scheltens P, Lammertsma AA. Evaluation of reference regions for (R)-[11C]PK11195 studies in Alzheimer's disease and mild cognitive impairment. J. Cereb. Blood Flow Metab. 2007; 27(12): 1965-1974.
Schuitemaker A, van Berckel BNM, Kropholler MA, Kloet RW, Jonker C, Scheltens P, Lammertsma AA, Boellaard R. Evaluation of methods for generating parametric (R)-[11C]PK11195 binding images. J Cereb Blood Flow Metab. 2007a; 1603-1615.
Schuitemaker A, van Berckel BN, Kropholler MA, Veltman DJ, Scheltens P, Jonker C, Lammertsma AA, Boellaard R. SPM analysis of parametric (R)-[11C]PK11195 binding images: plasma input versus reference tissue parametric methods. Neuroimage 2007b; 35(4): 1473-1479.
Schuitemaker A, Kropholler MA, Boellaard R, van der Flier WM, Kloet RW, van der Doef TF, Knol DL, Windhorst AD, Luurtsema G, Barkhof F, Jonker C, Lammertsma AA, Scheltens P, van Berckel BNM. Microglial activation in Alzheimer's disease: an (R)-[11C]PK11195 positron emission tomography study. Neurobiol Aging 2012 (in press).
Tomasi G, Edison P, Bertoldo A, Roncaroli F, Singh P, Gerhard A, Cobelli C, Brooks DJ, Turkheimer FE. 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: 1249-1256.
Turkheimer FE, Edison P, Pavese N, Roncaroli F, Anderson AN, Hammers A, Gerhard A, Hinz R, Tai YF, Brooks DJ. Reference and target region modeling of [11C](R)-PK11195 brain studies. J. Nucl. Med. 2007; 48(1): 158-167.