- Email: [email protected]
FLUTRICICLAMIDE ([18F]GE180) PET: FIRST IN HUMAN PET STUDY OF NOVEL IN VIVO MARKER OF HUMAN TRANSLATOR PROTEIN
Poster Presentations: Sunday, July 24, 2016
P1-001
SUNDAY, JULY 24, 2016 POSTER PRESENTATIONS P1 FLUTRICICLAMIDE ([18F]GE180) PET: FIRST IN HUMAN PET STUDY OF NOVEL IN VIVO MARKER OF HUMAN TRANSLATOR PROTEIN
Zhen Fan1, Paul Edison1, Rebecca Atkinson1, Grazia Daniela Femminella1, Valeria Calsolaro1, Adam Waldman1, Chris J. Buckley2, William Trigg3, David J. Brooks1, Rainer Hinz4, 1Imperial College London, London, United Kingdom; 2GE Healthcare, Amersham, United Kingdom; 3GE Healthcare, Amersham, United Kingdom; 4University of Manchester, Manchester, United Kingdom. Contact e-mail: [email protected] Background: Neuroinflammation is associated with neurodegenera-
tive disease. PET radioligands targeting the 18 kDa translocator protein (TSPO) has been used as in vivo markers of neuroinflammation, but there is an urgent need for novel probes with an improved signal-to-noise ratio. Flutriciclamide (18F-GE180) is a recently developed third generation TSPO ligand. In this first study, we evaluated the optimum scan duration and kinetic modeling strategies for 18F-GE180 PET in (older) healthy controls. Methods: Ten healthy controls, six TSPO high affinity binders (HABs) and four mixed affinity binders (MABs), were recruited. All subjects had detailed neuropsychological tests and MRI, followed by a 210 min 18F-GE180 dynamic PET/CT scan using a metabolite corrected arterial plasma input function. Five different kinetic models describing brain 18F-GE180 uptake were interrogated: irreversible and reversible two-tissue compartment models, a reversible one-tissue model and two models with an extra irreversible vascular compartment. The optimum scan length was investigated based on 210 min scan data. The feasibility of generating parametric maps was also investigated using graphical analysis. Results: 18FGE180 concentration was higher in plasma than in whole blood during the entire scan duration. Using the kinetic models, the volume of distribution (VT) was 0.17 in HABs and 0.12 in MABs. The model that best represented brain 18F-GE180 kinetics across regions was the reversible two-tissue model and 90 min was determined as the optimum scan length required to obtain stable estimates. Logan graphical analysis with arterial input function gave a VThighly consistent with 2TCM4k, which could be used for voxel-wise analysis. Conclusions: We report here for the first time the kinetic properties of the novel 3nd generation TSPO PET ligand, 18 F-GE180, in humans: 2TCM4k is the optimal method to quantify the brain uptake and 90 min is the optimal scan length, and Logan approach could be used to generate parametric maps. While these control subjects have shown relatively low VT, the methodology presented in this study forms the basis for quantification of future PET studies using 18F-GE180 in different pathologies.
P397
heimer’s disease (AD). In the brain, TREM2 is highly expressed by microglia. TREM2 appears to mediate microglial phagocytosis and the expression of an anti-inflammatory phenotype. Loss of this function may contribute to the pathogenesis of AD and shift cell behaviour towards a more harmful pro-inflammatory phenotype. An important goal is to establish whether AD patients with/without a TREM2 risk variant share a similar microglial response to pathology. Methods: Human brain sections containing the hippocampal regions CA1 and CA4 were obtained from comparable AD cases with (AD/TREM2+) and without (AD/TREM2-) TREM2 variants, and Control/healthy cases without TREM2 variants (Control/TREM2-). Immunohistochemistry was performed using established antibodies to label microglia: anti-CD68, anti-HLA-DP, -DQ, or -DR (henceforth called HLA), and anti-Iba-1. We compared the abundance of immunolabelled microglia and their morphology to assess cell activation. Results: In line with published evidence, we observed more CD68+ and HLA+ microglia in the hippocampus of AD/TREM2- cases compared to Control/TREM2- cases. However, AD/TREM2+ cases had significantly fewer CD68+ and HLA+ microglia compared to AD/TREM2- and Control/TREM2cases. By comparison, the abundance of Iba-1+microglia was similar across the three groups. Microglia in AD/TREM2+ cases were more amoeboid than AD/TREM2- cases, which in turn were more amoeboid than Control/TREM2- cases suggesting some measures of cell activation were not impaired. Conclusions: AD-associated TREM2 variants seem to dampen the expression of important markers of cell activation in the presence of AD pathology. This does not appear to prevent the formation of cells with an activated morphology, in agreement with previously published observations in TREM2 knockout animal models. However, it does provide important insights in to the effects of TREM2 dysfunction on phagocytosis (CD68) and the adaptive immune responses (HLA-DR) both of which may impact on AD. Furthermore, it highlights important differences between sporadic AD and AD patients carrying a TREM2 risk variant, which might have implications for strategies which target neuroinflammation to treat AD.
P1-003
KNOCKDOWN OF TREM2 EXPRESSION IN MICROGLIA: IMPLICATIONS FOR MIGRATION AND INFLAMMATION
Alexandra Phillips1, Claudio Villegas Llerena1, Thomas Piers2, Matt Butler2, John Hardy3, Jennifer M. Pocock1, 1Institute of Neurology, UCL, London, United Kingdom; 2Therapeutic Innovation Group, Translational Research Office, UCL, London, United Kingdom; 3 UCL Institute of Neurology, London, United Kingdom. Contact e-mail: [email protected] Background: Microglial responses critically underpin pathological
P1-002
AD-ASSOCIATED TREM2 VARIANTS LEAD TO SOME SUBPOPULATIONS OF MICROGLIA TO BE LESS ABUNDANT BUT MORE ACTIVATED
Yau Mun Lim1, Anaelle Dumas1, Andrew King2, Claire Troakes3, Christina E. Murray4, Kuang Lin1, Safa Al-Sarraj2, Lawrence Sivakumar1, Tammaryn Lashley5, Angela Hodges1, 1King’s College London, Institute of Psychiatry, Psychology & Neuroscience, London, United Kingdom; 2Kings College NHS Foundation Trust, London, United Kingdom; 3King’s College London, London, United Kingdom; 4University College London, Institute of Neurology, London, United Kingdom; 5University College London, London, United Kingdom. Contact e-mail: [email protected] Background: Variants in the triggering receptor expressed on
myeloid cells 2 (TREM2) gene increase the risk of developing Alz-
processes associated with progressive neurodegenerative diseases including Alzheimer’s and Parkinson’s diseases. Regulated inflammation is essential in the healthy brain however, prolonged inflammation, attributed to dysregulated microglial activation, is implicated in the pathogenesis of progressive neurodegeneration. Recent genome-wide association studies have identified mutations in the gene for triggering receptor expressed on myeloid cells (TREM2) as putative risk factors for late-onset Alzheimer’s disease (LOAD) (Guerreiro et al., 2013; Jonsson et al 2013). TREM2 is a major microglia-specific gene, ranked #31 of the most highly expressed microglia receptors. TREM2 may act as a lock to repress microglial pro-inflammatory activity, whilst promoting protective microglial responses such as chemotaxis and phagocytosis.
P1-001
SUNDAY, JULY 24, 2016 POSTER PRESENTATIONS P1 FLUTRICICLAMIDE ([18F]GE180) PET: FIRST IN HUMAN PET STUDY OF NOVEL IN VIVO MARKER OF HUMAN TRANSLATOR PROTEIN
Zhen Fan1, Paul Edison1, Rebecca Atkinson1, Grazia Daniela Femminella1, Valeria Calsolaro1, Adam Waldman1, Chris J. Buckley2, William Trigg3, David J. Brooks1, Rainer Hinz4, 1Imperial College London, London, United Kingdom; 2GE Healthcare, Amersham, United Kingdom; 3GE Healthcare, Amersham, United Kingdom; 4University of Manchester, Manchester, United Kingdom. Contact e-mail: [email protected] Background: Neuroinflammation is associated with neurodegenera-
tive disease. PET radioligands targeting the 18 kDa translocator protein (TSPO) has been used as in vivo markers of neuroinflammation, but there is an urgent need for novel probes with an improved signal-to-noise ratio. Flutriciclamide (18F-GE180) is a recently developed third generation TSPO ligand. In this first study, we evaluated the optimum scan duration and kinetic modeling strategies for 18F-GE180 PET in (older) healthy controls. Methods: Ten healthy controls, six TSPO high affinity binders (HABs) and four mixed affinity binders (MABs), were recruited. All subjects had detailed neuropsychological tests and MRI, followed by a 210 min 18F-GE180 dynamic PET/CT scan using a metabolite corrected arterial plasma input function. Five different kinetic models describing brain 18F-GE180 uptake were interrogated: irreversible and reversible two-tissue compartment models, a reversible one-tissue model and two models with an extra irreversible vascular compartment. The optimum scan length was investigated based on 210 min scan data. The feasibility of generating parametric maps was also investigated using graphical analysis. Results: 18FGE180 concentration was higher in plasma than in whole blood during the entire scan duration. Using the kinetic models, the volume of distribution (VT) was 0.17 in HABs and 0.12 in MABs. The model that best represented brain 18F-GE180 kinetics across regions was the reversible two-tissue model and 90 min was determined as the optimum scan length required to obtain stable estimates. Logan graphical analysis with arterial input function gave a VThighly consistent with 2TCM4k, which could be used for voxel-wise analysis. Conclusions: We report here for the first time the kinetic properties of the novel 3nd generation TSPO PET ligand, 18 F-GE180, in humans: 2TCM4k is the optimal method to quantify the brain uptake and 90 min is the optimal scan length, and Logan approach could be used to generate parametric maps. While these control subjects have shown relatively low VT, the methodology presented in this study forms the basis for quantification of future PET studies using 18F-GE180 in different pathologies.
P397
heimer’s disease (AD). In the brain, TREM2 is highly expressed by microglia. TREM2 appears to mediate microglial phagocytosis and the expression of an anti-inflammatory phenotype. Loss of this function may contribute to the pathogenesis of AD and shift cell behaviour towards a more harmful pro-inflammatory phenotype. An important goal is to establish whether AD patients with/without a TREM2 risk variant share a similar microglial response to pathology. Methods: Human brain sections containing the hippocampal regions CA1 and CA4 were obtained from comparable AD cases with (AD/TREM2+) and without (AD/TREM2-) TREM2 variants, and Control/healthy cases without TREM2 variants (Control/TREM2-). Immunohistochemistry was performed using established antibodies to label microglia: anti-CD68, anti-HLA-DP, -DQ, or -DR (henceforth called HLA), and anti-Iba-1. We compared the abundance of immunolabelled microglia and their morphology to assess cell activation. Results: In line with published evidence, we observed more CD68+ and HLA+ microglia in the hippocampus of AD/TREM2- cases compared to Control/TREM2- cases. However, AD/TREM2+ cases had significantly fewer CD68+ and HLA+ microglia compared to AD/TREM2- and Control/TREM2cases. By comparison, the abundance of Iba-1+microglia was similar across the three groups. Microglia in AD/TREM2+ cases were more amoeboid than AD/TREM2- cases, which in turn were more amoeboid than Control/TREM2- cases suggesting some measures of cell activation were not impaired. Conclusions: AD-associated TREM2 variants seem to dampen the expression of important markers of cell activation in the presence of AD pathology. This does not appear to prevent the formation of cells with an activated morphology, in agreement with previously published observations in TREM2 knockout animal models. However, it does provide important insights in to the effects of TREM2 dysfunction on phagocytosis (CD68) and the adaptive immune responses (HLA-DR) both of which may impact on AD. Furthermore, it highlights important differences between sporadic AD and AD patients carrying a TREM2 risk variant, which might have implications for strategies which target neuroinflammation to treat AD.
P1-003
KNOCKDOWN OF TREM2 EXPRESSION IN MICROGLIA: IMPLICATIONS FOR MIGRATION AND INFLAMMATION
Alexandra Phillips1, Claudio Villegas Llerena1, Thomas Piers2, Matt Butler2, John Hardy3, Jennifer M. Pocock1, 1Institute of Neurology, UCL, London, United Kingdom; 2Therapeutic Innovation Group, Translational Research Office, UCL, London, United Kingdom; 3 UCL Institute of Neurology, London, United Kingdom. Contact e-mail: [email protected] Background: Microglial responses critically underpin pathological
P1-002
AD-ASSOCIATED TREM2 VARIANTS LEAD TO SOME SUBPOPULATIONS OF MICROGLIA TO BE LESS ABUNDANT BUT MORE ACTIVATED
Yau Mun Lim1, Anaelle Dumas1, Andrew King2, Claire Troakes3, Christina E. Murray4, Kuang Lin1, Safa Al-Sarraj2, Lawrence Sivakumar1, Tammaryn Lashley5, Angela Hodges1, 1King’s College London, Institute of Psychiatry, Psychology & Neuroscience, London, United Kingdom; 2Kings College NHS Foundation Trust, London, United Kingdom; 3King’s College London, London, United Kingdom; 4University College London, Institute of Neurology, London, United Kingdom; 5University College London, London, United Kingdom. Contact e-mail: [email protected] Background: Variants in the triggering receptor expressed on
myeloid cells 2 (TREM2) gene increase the risk of developing Alz-
processes associated with progressive neurodegenerative diseases including Alzheimer’s and Parkinson’s diseases. Regulated inflammation is essential in the healthy brain however, prolonged inflammation, attributed to dysregulated microglial activation, is implicated in the pathogenesis of progressive neurodegeneration. Recent genome-wide association studies have identified mutations in the gene for triggering receptor expressed on myeloid cells (TREM2) as putative risk factors for late-onset Alzheimer’s disease (LOAD) (Guerreiro et al., 2013; Jonsson et al 2013). TREM2 is a major microglia-specific gene, ranked #31 of the most highly expressed microglia receptors. TREM2 may act as a lock to repress microglial pro-inflammatory activity, whilst promoting protective microglial responses such as chemotaxis and phagocytosis.