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In vivo imaging of amyloid plaques by MRI after IV administration of a contrast agent
P10 IC-O3-02
IC Oral Sessions: IC-O3: Panel Session: Novel Tracers and Techniques for Imaging In Alzheimer’s DEVELOPMENT OF A CAA-SPECIFIC AMYLOID IMAGING TRACER
Byung-Hee Han, Wenhua Chu, Jinbin Xu, Robert Mach, Gregory Zipfel, Washington University School of Medicine, St. Louis, Missouri, United States. Background: Cerebral amyloid angiopathy (CAA) is a well recognized cause of lobar cerebral hemorrhage, ischemic stroke, and cognitive dysfunction both in AD and non-AD patient populations. Yet to date only “possible” or “probable” diagnosis of CAA has been achievable without obtaining pathological tissue via brain biopsy or at autopsy. Though amyloid tracers labeled with positron-emitting radioligands have shown promise for non-invasive amyloid imaging in AD patients, they have been unable to clarify whether the observed amyloid load represents neuritic plaques vs. CAA due to the low resolution of PET imaging and the almost equal affinity of these tracers for both vascular and parenchymal amyloid. Recently, we demonstrated that phenoxazine analogs preferentially bind CAA over neuritic plaques in postmortem AD brain tissues as well as in aged Tg2576 mice (Han et al, Molecular Neurodegeneration 6:86, 2011). Though the molecular basis underlying their selective binding to CAA remains elusive, this unique binding specificity suggests that this type of compound has great potential as a CAA-specific amyloid tracer that will permit non-invasive diagnosis of CAA, quantitation of CAA severity, and monitoring of CAA progression over time. Methods: To further explore this possibility, we synthesized a series of new phenoxazine analogs based on our preliminary structure-activity relationship data. We determined the binding affinity (Ki values) of these novel compounds on CAA isolated from Tg2576 mice utilizing a competitive binding assay system with a [3H]phenoxazine ligand. We next performed an in situ competitive binding assay to determine their selective binding affinity for CAA over neuritic plaques in brain tissues of aged Tg2576 mice having both CAA deposits and neuritic plaques. The lipophilicity of phenoxazine derivatives was determined by octanol-water coefficient to predict their brain accessibility. Results: We found that phenoxazine derivatives, in particular 5-5, revealed enhanced binding affinity for CAA as compared with the parental compound. More importantly, synthesized phenoxazine analogs preserved the preferential binding affinity for CAA over neuritic plaques. Conclusions: These results strongly suggest that phenoxazine analogs provide great potential for development of a CAA-specific amyloid tracer that would be a major diagnostic step forward for this frequent (but often under-diagnosed) condition. IC-O3-03
IN VIVO IMAGING OF AMYLOID PLAQUES BY MRI AFTER IV ADMINISTRATION OF A CONTRAST AGENT
Mathieu David Santin1, Thomas Debeir2, Thomas Rooney2, Marc Dhenain3, 1URA CEA CNRS 2210, Fontenay-aux-Roses, France; 2 Sanofi-Aventis, Chilly-Mazarin, France; 3CNRS Fontenay-aux-Roses, France. Background: Magnetic resonance imaging (MRI) combined with intracerebro-ventricular administration of Gadolinium (Gd-DOTA) contrast agents can be used to detect individual amyloid plaques in transgenic live mice (ICV-Gd-Staining protocol [Petiet, in press]). Here, we implemented a new protocol to detect amyloid plaques by MRI after IV administration of the contrast agent. Methods: The ability to detect amyloid plaques after IV administration of a contrast agent requires the opening of the blood-brain barrier (BBB). Some studies showed the feasibility of BBB opening with the use of ultrasound (US) and ultrasound contrast agents (encapsulated gas microbubbles) [Howles, 2010;
Mc Dannold, 2007]. Under the action of an ultrasound beam, microbubbles oscillate and allow the opening of the BBB. In the current study, BBB opening was obtained by means of a controlled acoustic excitation leaded by an unfocalized ultrasound transducer (Imasonic) and encapsulated gas microbubbles (Sonovue, Bracco) injected IV. NMR contrast agent (Dotarem, Guerbet) was IV-injected (US-Gd-staining protocol). 3D Gradient-echo NMR images (TR/TE ¼ 30/15ms, resolution: 29x29x117 mm3, Nex ¼ 1, scan time: 32 min; 7T-Varian) were recorded. The study was done using 6 APP/PS1 transgenic mice (8 to 17 monthsold) exhibiting cerebral amyloid plaques and 6 control (littermate, PS1) plaque-free mice. Results: US-Gd-staining, but also in vivo ICV-Gdstaining largely increased the signal to noise ratio in the brain images of mice. No hypointense spots which could be falsely identified as plaques were detected within the brain of amyloid-free littermate mice with the ICV-Gd-staining or US-Gd-staining methods. In transgenic mice, hypointense spots could be detected in the cortex of all animals imaged with in vivo US-Gd-staining (Fig. 1, Left panel, arrows) and in vivo ICV-Gd-staining (Fig. 1, right panel). The hypointense spots could be correlated to amyloid plaques as detected on histological sections. These lesions were identified even in the youngest mice used in this study (8-months old). Conclusions: To our knowledge this is the first study showing the feasibility of amyloid plaque imaging in mouse with a peripheric injection of NMR contrast agent and the non invasive opening of the BBB by U.S.
IC-O3-04
AMYLOID PET IMAGING USING AZD4694 AND UNUSUALLY BRIEF RADIOTRACER UPTAKE AND SCANNING PERIODS
Kewei Chen1, Jessica B. Langbaum1, Adam S. Fleisher1, Auttawut Roontiva1, Xiaofen Liu1, Pradeep Thiyyagura1, Dan Bandy1, Nicole Richter1, Laura Jakimovich1, Anita Prouty1, Zsolt Cselenyi2, Lars Farde2, Samantha Budd2, Eric M. Reiman1, 1Banner Alzheimer’s Institute, Phoenix, Arixona, United States; 2AstraZeneca R&D, Sodertalje, Sweden. Background: AZD4694 is a second-generation [18F]-labeled amyloid PET ligand associated with relatively rapid uptake and equilibrium in brain and which appears to have relatively high specific-to-white matter binding. In this study, we compared the use of PET frames acquired at different times following radiotracer administration, roughly corresponding to the average time associated with peak specific binding in gray matter (i.e. maximal cerebral-to-cerebellar uptake difference), and with different durations. Methods: Dynamic 90-minute AZD4694 PET scans were performed in 10 patients with probable AD, 10 cognitively normal older adults, and 4 cognitively normal young adult APOEe4 noncarriers. Preselected regions-of-interest and an automated brain mapping algorithm were each used to characterize and compare the ability of AZD4694 standard uptake value ratios (SUVRs) to distinguish the probable AD patients from the cognitively normal older and younger adults using 20-30 min, 20-25, 25-30, and 25-35 min frames. Results: PET frames from each of the selected intervals used in this study was able to distinguish the probable AD group from the older and younger controls groups (P<0.05) using either mean cortical SUVRs or brain maps. Voxel-wise analysis revealed a spatial pattern of amyloid deposition typically observed in patients with pAD. Conclusions: While larger studies are needed to compare the ability of different time intervals to distinguish subject groups with greater statistical power, AZD4694 could help characterize cerebral amyloid deposition with a radiotracer uptake period as brief as 20 min and an emission fame as brief as 5 min, a feature that may have practical advantages in certain settings.
IC Oral Sessions: IC-O3: Panel Session: Novel Tracers and Techniques for Imaging In Alzheimer’s DEVELOPMENT OF A CAA-SPECIFIC AMYLOID IMAGING TRACER
Byung-Hee Han, Wenhua Chu, Jinbin Xu, Robert Mach, Gregory Zipfel, Washington University School of Medicine, St. Louis, Missouri, United States. Background: Cerebral amyloid angiopathy (CAA) is a well recognized cause of lobar cerebral hemorrhage, ischemic stroke, and cognitive dysfunction both in AD and non-AD patient populations. Yet to date only “possible” or “probable” diagnosis of CAA has been achievable without obtaining pathological tissue via brain biopsy or at autopsy. Though amyloid tracers labeled with positron-emitting radioligands have shown promise for non-invasive amyloid imaging in AD patients, they have been unable to clarify whether the observed amyloid load represents neuritic plaques vs. CAA due to the low resolution of PET imaging and the almost equal affinity of these tracers for both vascular and parenchymal amyloid. Recently, we demonstrated that phenoxazine analogs preferentially bind CAA over neuritic plaques in postmortem AD brain tissues as well as in aged Tg2576 mice (Han et al, Molecular Neurodegeneration 6:86, 2011). Though the molecular basis underlying their selective binding to CAA remains elusive, this unique binding specificity suggests that this type of compound has great potential as a CAA-specific amyloid tracer that will permit non-invasive diagnosis of CAA, quantitation of CAA severity, and monitoring of CAA progression over time. Methods: To further explore this possibility, we synthesized a series of new phenoxazine analogs based on our preliminary structure-activity relationship data. We determined the binding affinity (Ki values) of these novel compounds on CAA isolated from Tg2576 mice utilizing a competitive binding assay system with a [3H]phenoxazine ligand. We next performed an in situ competitive binding assay to determine their selective binding affinity for CAA over neuritic plaques in brain tissues of aged Tg2576 mice having both CAA deposits and neuritic plaques. The lipophilicity of phenoxazine derivatives was determined by octanol-water coefficient to predict their brain accessibility. Results: We found that phenoxazine derivatives, in particular 5-5, revealed enhanced binding affinity for CAA as compared with the parental compound. More importantly, synthesized phenoxazine analogs preserved the preferential binding affinity for CAA over neuritic plaques. Conclusions: These results strongly suggest that phenoxazine analogs provide great potential for development of a CAA-specific amyloid tracer that would be a major diagnostic step forward for this frequent (but often under-diagnosed) condition. IC-O3-03
IN VIVO IMAGING OF AMYLOID PLAQUES BY MRI AFTER IV ADMINISTRATION OF A CONTRAST AGENT
Mathieu David Santin1, Thomas Debeir2, Thomas Rooney2, Marc Dhenain3, 1URA CEA CNRS 2210, Fontenay-aux-Roses, France; 2 Sanofi-Aventis, Chilly-Mazarin, France; 3CNRS Fontenay-aux-Roses, France. Background: Magnetic resonance imaging (MRI) combined with intracerebro-ventricular administration of Gadolinium (Gd-DOTA) contrast agents can be used to detect individual amyloid plaques in transgenic live mice (ICV-Gd-Staining protocol [Petiet, in press]). Here, we implemented a new protocol to detect amyloid plaques by MRI after IV administration of the contrast agent. Methods: The ability to detect amyloid plaques after IV administration of a contrast agent requires the opening of the blood-brain barrier (BBB). Some studies showed the feasibility of BBB opening with the use of ultrasound (US) and ultrasound contrast agents (encapsulated gas microbubbles) [Howles, 2010;
Mc Dannold, 2007]. Under the action of an ultrasound beam, microbubbles oscillate and allow the opening of the BBB. In the current study, BBB opening was obtained by means of a controlled acoustic excitation leaded by an unfocalized ultrasound transducer (Imasonic) and encapsulated gas microbubbles (Sonovue, Bracco) injected IV. NMR contrast agent (Dotarem, Guerbet) was IV-injected (US-Gd-staining protocol). 3D Gradient-echo NMR images (TR/TE ¼ 30/15ms, resolution: 29x29x117 mm3, Nex ¼ 1, scan time: 32 min; 7T-Varian) were recorded. The study was done using 6 APP/PS1 transgenic mice (8 to 17 monthsold) exhibiting cerebral amyloid plaques and 6 control (littermate, PS1) plaque-free mice. Results: US-Gd-staining, but also in vivo ICV-Gdstaining largely increased the signal to noise ratio in the brain images of mice. No hypointense spots which could be falsely identified as plaques were detected within the brain of amyloid-free littermate mice with the ICV-Gd-staining or US-Gd-staining methods. In transgenic mice, hypointense spots could be detected in the cortex of all animals imaged with in vivo US-Gd-staining (Fig. 1, Left panel, arrows) and in vivo ICV-Gd-staining (Fig. 1, right panel). The hypointense spots could be correlated to amyloid plaques as detected on histological sections. These lesions were identified even in the youngest mice used in this study (8-months old). Conclusions: To our knowledge this is the first study showing the feasibility of amyloid plaque imaging in mouse with a peripheric injection of NMR contrast agent and the non invasive opening of the BBB by U.S.
IC-O3-04
AMYLOID PET IMAGING USING AZD4694 AND UNUSUALLY BRIEF RADIOTRACER UPTAKE AND SCANNING PERIODS
Kewei Chen1, Jessica B. Langbaum1, Adam S. Fleisher1, Auttawut Roontiva1, Xiaofen Liu1, Pradeep Thiyyagura1, Dan Bandy1, Nicole Richter1, Laura Jakimovich1, Anita Prouty1, Zsolt Cselenyi2, Lars Farde2, Samantha Budd2, Eric M. Reiman1, 1Banner Alzheimer’s Institute, Phoenix, Arixona, United States; 2AstraZeneca R&D, Sodertalje, Sweden. Background: AZD4694 is a second-generation [18F]-labeled amyloid PET ligand associated with relatively rapid uptake and equilibrium in brain and which appears to have relatively high specific-to-white matter binding. In this study, we compared the use of PET frames acquired at different times following radiotracer administration, roughly corresponding to the average time associated with peak specific binding in gray matter (i.e. maximal cerebral-to-cerebellar uptake difference), and with different durations. Methods: Dynamic 90-minute AZD4694 PET scans were performed in 10 patients with probable AD, 10 cognitively normal older adults, and 4 cognitively normal young adult APOEe4 noncarriers. Preselected regions-of-interest and an automated brain mapping algorithm were each used to characterize and compare the ability of AZD4694 standard uptake value ratios (SUVRs) to distinguish the probable AD patients from the cognitively normal older and younger adults using 20-30 min, 20-25, 25-30, and 25-35 min frames. Results: PET frames from each of the selected intervals used in this study was able to distinguish the probable AD group from the older and younger controls groups (P<0.05) using either mean cortical SUVRs or brain maps. Voxel-wise analysis revealed a spatial pattern of amyloid deposition typically observed in patients with pAD. Conclusions: While larger studies are needed to compare the ability of different time intervals to distinguish subject groups with greater statistical power, AZD4694 could help characterize cerebral amyloid deposition with a radiotracer uptake period as brief as 20 min and an emission fame as brief as 5 min, a feature that may have practical advantages in certain settings.