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Test–retest reliability of [18F]PBR111 binding to translocator protein (TSPO) in young healthy control subjects
S214
P.1.f. Basic and clinical neuroscience − Neuro-immune interaction
P.1.f.011 Test–retest reliability of [18 F]PBR111 binding to translocator protein (TSPO) in young healthy control subjects L. De Picker1 ° , J. Ottoy2 , S. Deleye2 , J. Verhaeghe2 , S. Stroobants2 , L. Wyffels2 , S. Dedeurwaerdere3 , M. Morrens1 , S. Staelens2 1 University of Antwerp, Collaborative Antwerp Psychiatric Research Institute, Antwerp Wilrijk, Belgium; 2 University of Antwerp/University Hospital Antwerp, Molecular Imaging Center Antwerp, Antwerp Wilrijk, Belgium; 3 University of Antwerp, Experimental LAB TNS-ORL, Antwerp Wilrijk, Belgium Background: Positron-emission tomography (PET) with radioligand [18 F]PBR111 has been used in neuropsychiatric disorders for the imaging of the translocator protein (TSPO), as a means to map activated microglial cells in the brain. Longitudinal monitoring of changes in TSPO binding is of great clinical interest. Aim: To examine the test-retest variability of the total volume of distribution (VT) of [18 F]PBR111 PET binding in healthy subjects. Method: [18 F]PBR111 binding was examined by 90-minute dynamic PET-CT scan in ten healthy male subjects (age 26.4±4.8 y) at two separate occasions, 7−40 weeks apart and at the same time of day. Coregistration with 3D T1-weighted MRI images was used to define anatomical regions. Regional VT were derived using a region-of-interest based two-tissue compartmental analysis (2TCM) with an additional vascular trapping component [1] and correction for partial-volume effects. A continuous [18 F]PBR111 arterial input function over the first 5 minutes was complemented by 8 manual samples and corrected for metabolites. Prior genotyping of subjects for the rs6917 polymorphism distinguished high- (HAB, n = 4) and mixed-affinity binders (MAB, n = 6). The absolute test-retest variability was calculated as the absolute difference in VT between the first and second scans, relative to the mean of the two values. A two-way mixed model reliability analysis for absolute agreement was performed in SPSS 22.0 to calculate intraclass correlation coefficients (ICC). Results: Mean absolute variability in VT was 16.7±14.6% (HAB 19.2%; MAB 15.5%) in cortical grey matter (GM) regions and 18.2±14.7% (HAB 20.1%, MAB 16.7%) in cortical white matter (WM) regions. ICCs were consistently between 0.79–0.87 for all regions of interest (see table). Table: Comparison of ICC values in different regions over three studies ICC value Tracer + model used [18 F]PBR111 2TCM + [11 C]PBR28 2TCM [2] [11 C](R)-PK11195 2TCM [3] vascular trapping Cortical GM Cortical WM Basal Ganglia Thalamus Hippocampus Cerebellum
0.83* 0.79* 0.85* 0.85* 0.87* 0.83*
0.92 0.32 0.90 0.91 0.94
0.47 0.73 0.09 −0.06 0.07
*p0.01.
Discussion: An earlier study on test-retest variability with first-generation TSPO ligand [11 C](R)-PK11195 concluded that whereas the reproducibility of PK11195 binding in large brain regions was acceptable, use of this ligand is limited for detailed mapping of TSPO changes in smaller brain regions [3]. It appears that second-generation TSPO tracers can achieve improved reproducibility results, even in small brain regions. In our own study with [18 F]PBR111 as well as in a recently published study
with [11 C]PBR28, both second generation ligands, markedly better ICCs were found compared to those of [11 C](R)-PK11195 (see table). Both in terms of reliability and mean absolute variability, the [18 F]PBR111 binding reproducibility in cortical GM was similar to that of [11 C]PBR28 (mean absolute variability 18.3 ± 12.7% [2]), and outperformed [11 C]PBR28 in cortical WM (mean absolute variability 48.3±39.8% [2]). Conclusion: [18 F]PBR111 can be used for longitudinal monitoring of TSPO binding in both large and small brain regions, as shown by medium to low test-retest variability and high reliability of VT in healthy controls. This allows TSPO binding to be used as a biomarker for the evaluation of novel treatments and for the follow-up of disease progression in many neuropsychiatric illnesses. References [1] Rizzo G, Veronese M, Tonietto M et al, 2014. Kinetic modeling without accounting for the vascular component impairs the quantification of [(11)C]PBR28 brain PET data. J Cereb Blood Flow Metab 34, 1060−9. [2] Collste K, Forsberg A, Varrone A et al, 2016. Test-retest reproducibility of [(11)C]PBR28 binding to TSPO in healthy control subjects. Eur J Nucl Med Mol Imaging 43, 173−83. [3] Juˇcaite A1, Csel´enyi Z, Arvidsson A et al, 2012. Kinetic analysis and test-retest variability of the radioligand [11 C](R)-PK11195 binding to TSPO in the human brain − a PET study in control subjects. EJNMMI Res 23, 15.
P.1.f.012 Suppression of splenic natural killer cell activity and number in 6-OHDA-induced rat model of Parkinson’s disease B. Grembecka1 ° , W. Glac1 , P. Badtke2 , G. Jerzemowska1 , K. Plucinska1 , D. Wrona1 1 University of Gdansk- Faculty of Biology, Department of Animal and Human Physiology, Gdansk, Poland; 2 Medical University of Gdansk, Department of Physiology, Gdansk, Poland Background: Parkinson’s disease (PD) is a neurodegenerative disorder caused by the loss of dopaminergic neurons in the substantia nigra (SN). Besides the motor dysfunction, most of PD patients have altered peripheral immune system functions [1] and developed peripheral neuropathy [2]. Animal experiments showed, that activation of blood immune parameters after bilateral intrastriatal administration of the neurotoxin 6-hydroxydopamine (6-OHDA) are time dependent [3]. The objective of our study was to examine a splenic natural killer (NK) cell number and function in rats with unilateral neurotoxic lesion of SN, which may reflect the late animal model of PD. Methods: Male Wistar rats (9 per group) were randomly assigned to two experimental groups: group I (VEH) received a single 4-ml intranigral infusion (into right substantia nigra pars compacta) of ascorbic acid (0.05%) as vehicle, while group II (6-OHDA) received 3mg/ml of 6-OHDA in ascorbic acid for 4 min (1 ml/min). Three weeks later, animals were overdosed with sodium pentobarbital and spleens were isolated. Spleen mononuclear cells as effector cells (E) and YAC-1 (Maloneyvirusinduced lymphoma) as target cells (T) were used in natural killer cell cytotoxicity (NKCC) assay, using a 51Cr-release. Target cells were cultured with various concentrations of effector cells (E/T = 50:1, 25:1, 12:1) as previously described in detail [4]. Spleen NK cells number were determined by flow cytometry (CD3-FITC/CD45RA-PC7/CD161a-APC). PD model have been verified by the immunohistochemical detection of tyrosine hydroxylase positive neurons (TH+) in substantia nigra pars compacta
P.1.f. Basic and clinical neuroscience − Neuro-immune interaction
P.1.f.011 Test–retest reliability of [18 F]PBR111 binding to translocator protein (TSPO) in young healthy control subjects L. De Picker1 ° , J. Ottoy2 , S. Deleye2 , J. Verhaeghe2 , S. Stroobants2 , L. Wyffels2 , S. Dedeurwaerdere3 , M. Morrens1 , S. Staelens2 1 University of Antwerp, Collaborative Antwerp Psychiatric Research Institute, Antwerp Wilrijk, Belgium; 2 University of Antwerp/University Hospital Antwerp, Molecular Imaging Center Antwerp, Antwerp Wilrijk, Belgium; 3 University of Antwerp, Experimental LAB TNS-ORL, Antwerp Wilrijk, Belgium Background: Positron-emission tomography (PET) with radioligand [18 F]PBR111 has been used in neuropsychiatric disorders for the imaging of the translocator protein (TSPO), as a means to map activated microglial cells in the brain. Longitudinal monitoring of changes in TSPO binding is of great clinical interest. Aim: To examine the test-retest variability of the total volume of distribution (VT) of [18 F]PBR111 PET binding in healthy subjects. Method: [18 F]PBR111 binding was examined by 90-minute dynamic PET-CT scan in ten healthy male subjects (age 26.4±4.8 y) at two separate occasions, 7−40 weeks apart and at the same time of day. Coregistration with 3D T1-weighted MRI images was used to define anatomical regions. Regional VT were derived using a region-of-interest based two-tissue compartmental analysis (2TCM) with an additional vascular trapping component [1] and correction for partial-volume effects. A continuous [18 F]PBR111 arterial input function over the first 5 minutes was complemented by 8 manual samples and corrected for metabolites. Prior genotyping of subjects for the rs6917 polymorphism distinguished high- (HAB, n = 4) and mixed-affinity binders (MAB, n = 6). The absolute test-retest variability was calculated as the absolute difference in VT between the first and second scans, relative to the mean of the two values. A two-way mixed model reliability analysis for absolute agreement was performed in SPSS 22.0 to calculate intraclass correlation coefficients (ICC). Results: Mean absolute variability in VT was 16.7±14.6% (HAB 19.2%; MAB 15.5%) in cortical grey matter (GM) regions and 18.2±14.7% (HAB 20.1%, MAB 16.7%) in cortical white matter (WM) regions. ICCs were consistently between 0.79–0.87 for all regions of interest (see table). Table: Comparison of ICC values in different regions over three studies ICC value Tracer + model used [18 F]PBR111 2TCM + [11 C]PBR28 2TCM [2] [11 C](R)-PK11195 2TCM [3] vascular trapping Cortical GM Cortical WM Basal Ganglia Thalamus Hippocampus Cerebellum
0.83* 0.79* 0.85* 0.85* 0.87* 0.83*
0.92 0.32 0.90 0.91 0.94
0.47 0.73 0.09 −0.06 0.07
*p0.01.
Discussion: An earlier study on test-retest variability with first-generation TSPO ligand [11 C](R)-PK11195 concluded that whereas the reproducibility of PK11195 binding in large brain regions was acceptable, use of this ligand is limited for detailed mapping of TSPO changes in smaller brain regions [3]. It appears that second-generation TSPO tracers can achieve improved reproducibility results, even in small brain regions. In our own study with [18 F]PBR111 as well as in a recently published study
with [11 C]PBR28, both second generation ligands, markedly better ICCs were found compared to those of [11 C](R)-PK11195 (see table). Both in terms of reliability and mean absolute variability, the [18 F]PBR111 binding reproducibility in cortical GM was similar to that of [11 C]PBR28 (mean absolute variability 18.3 ± 12.7% [2]), and outperformed [11 C]PBR28 in cortical WM (mean absolute variability 48.3±39.8% [2]). Conclusion: [18 F]PBR111 can be used for longitudinal monitoring of TSPO binding in both large and small brain regions, as shown by medium to low test-retest variability and high reliability of VT in healthy controls. This allows TSPO binding to be used as a biomarker for the evaluation of novel treatments and for the follow-up of disease progression in many neuropsychiatric illnesses. References [1] Rizzo G, Veronese M, Tonietto M et al, 2014. Kinetic modeling without accounting for the vascular component impairs the quantification of [(11)C]PBR28 brain PET data. J Cereb Blood Flow Metab 34, 1060−9. [2] Collste K, Forsberg A, Varrone A et al, 2016. Test-retest reproducibility of [(11)C]PBR28 binding to TSPO in healthy control subjects. Eur J Nucl Med Mol Imaging 43, 173−83. [3] Juˇcaite A1, Csel´enyi Z, Arvidsson A et al, 2012. Kinetic analysis and test-retest variability of the radioligand [11 C](R)-PK11195 binding to TSPO in the human brain − a PET study in control subjects. EJNMMI Res 23, 15.
P.1.f.012 Suppression of splenic natural killer cell activity and number in 6-OHDA-induced rat model of Parkinson’s disease B. Grembecka1 ° , W. Glac1 , P. Badtke2 , G. Jerzemowska1 , K. Plucinska1 , D. Wrona1 1 University of Gdansk- Faculty of Biology, Department of Animal and Human Physiology, Gdansk, Poland; 2 Medical University of Gdansk, Department of Physiology, Gdansk, Poland Background: Parkinson’s disease (PD) is a neurodegenerative disorder caused by the loss of dopaminergic neurons in the substantia nigra (SN). Besides the motor dysfunction, most of PD patients have altered peripheral immune system functions [1] and developed peripheral neuropathy [2]. Animal experiments showed, that activation of blood immune parameters after bilateral intrastriatal administration of the neurotoxin 6-hydroxydopamine (6-OHDA) are time dependent [3]. The objective of our study was to examine a splenic natural killer (NK) cell number and function in rats with unilateral neurotoxic lesion of SN, which may reflect the late animal model of PD. Methods: Male Wistar rats (9 per group) were randomly assigned to two experimental groups: group I (VEH) received a single 4-ml intranigral infusion (into right substantia nigra pars compacta) of ascorbic acid (0.05%) as vehicle, while group II (6-OHDA) received 3mg/ml of 6-OHDA in ascorbic acid for 4 min (1 ml/min). Three weeks later, animals were overdosed with sodium pentobarbital and spleens were isolated. Spleen mononuclear cells as effector cells (E) and YAC-1 (Maloneyvirusinduced lymphoma) as target cells (T) were used in natural killer cell cytotoxicity (NKCC) assay, using a 51Cr-release. Target cells were cultured with various concentrations of effector cells (E/T = 50:1, 25:1, 12:1) as previously described in detail [4]. Spleen NK cells number were determined by flow cytometry (CD3-FITC/CD45RA-PC7/CD161a-APC). PD model have been verified by the immunohistochemical detection of tyrosine hydroxylase positive neurons (TH+) in substantia nigra pars compacta