- Email: [email protected]
Baseline amyloid PET imaging, longitudinal amyloid accumulation, and Tau PET imaging in preclinical Alzheimer's disease
Podium Presentations: Sunday, July 19, 2015 Des Neurotherapies Cellulaires et Moleculaires, Lausanne, Switzerland. Contact e-mail: [email protected] Background: We recently demonstrated the ability of lentiviral vectors encoding Tau proteins to generate genetic models of tauopathies in rodents. These data supported the development of a nonhuman primate model offering additional opportunities for the validation of imaging and biochemical biomarkers and the exploration of innovative therapies. Methods: 14 adult male Macaca fascicularis received bilateral stereotaxic injections of AAV vectors and overexpressing either the wild-type hTau1N4R (n¼5), the hTau1N4R P301L mutated form of Tau (n¼5) or a null GFP (n¼4) into the hippocampus (CA1). CSF and plasma samples were collected at 3, 5, 7 and 12 months post-injection (pi.). All animals underwent 18F-FDG and 18F-DPA714 PET imaging (FOCUS220, Siemens) 10-12 months after viral injection. Animals were sacrificed at 3 or 12 months pi. Results: Both constructs are able to drive neurodegenerative process throughout the brain with the progressive appearance of tangles in the hippocampus. Tau was found hyper and abnormally phosphorylated (AT8 and MC)1 immunoreactivities) at the injection site 3 months post-delivery and a progressive neurodegenerative process occurred also in connected areas. By PET, both Glucose metabolism and neuroinflammation are modified. Peripheral biomarkers are under analysis but inflammatory ones show some changes. Conclusions: This model of tauopathy holds great promise for further investigation of diagnostic and therapeutic strategies in non-human primates. Supported by Fondation Plan Alzheimer & LabEx DISTALZ. O1-06-05
BASELINE AMYLOID PET IMAGING, LONGITUDINAL AMYLOID ACCUMULATION, AND TAU PET IMAGING IN PRECLINICAL ALZHEIMER’S DISEASE
Aaron P. Schultz1,2, Elizabeth C. Mormino2,3, Jasmeer P. Chhatwal1,2, Molly LaPoint1, Alex S. Dagley4, Reisa A. Sperling1,2,5, Keith A. Johnson2,4, 1Massachusetts General Hospital and the Athinoula A. Martinos Center for Biomedical Imaging, Boston, MA, USA; 2Harvard Medical School, Boston, MA, USA; 3Massachusetts General Hospital, Boston, MA, USA; 4Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA; 5Brigham and Women’s Hospital, Boston, MA, USA. Contact e-mail: [email protected] Background: Amyloid-beta (Ab) plaque and tau neurofibrillary pa-
thologies both accumulate in cognitively normal elderly individuals and both can now be measured in vivo using PET. We tested whether measures of tau deposition were related to Ab burden or its retrospective 3-year accumulation rate in normal elderly. Methods: Eighty-three participants in the Harvard Aging Brain Study (HABS – P01AG036694; age¼76.166.1; baseline CDR¼0; e4+/e4- 19/56) underwent baseline and followup 11C PiB measurements of Ab over 3.261.2 years (with 2.56.7 visits per subject). Mean cortical PiB DVR and its change with time was compared with inferior temporal 18F T807 SUVR measures of tau We used Freesurfer ROIs, cerebellar grey reference, and the geometric transform metric (GTM) for partial volume correction. Age, gender, and the time between PiB and T807 imaging were included in all models. Results: We found significant relationships between inferior temporal T807 and either baseline PiB (t(78) ¼ 4.38; p<0.001) or rate of accumulation of PiB (t(78) ¼ 2.36; p¼0.008). When both baseline amyloid burden and rate of accumulation were included in the model, baseline amyloid burden re-
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mained significant (p<0.001) whereas rate of accumulation did not (p¼0.41). Based on model estimates (not including rate of amyloid accumulation), T807 increases by 0.1860.04 SUVR units for every 1 DVR increase in amyloid relative to a PiB value of 1.41, whereas age (p¼0.025) increases 0.00760.003 SUVR units per year relative to a reference age of 75.8. The same pattern of results held across entorhinal, parahippocampal, fusiform, inferior temporal, middle temporal, and inferior parietal ROIs, but was non-significant for superior temporal, superior parietal, or precuneus. Conclusions: Amyloid-beta and its w3-year accumulation rate are each associated with tau pathologic burden in cognitively normal elderly. However, Aß accumulation rate is low and does not provide stronger predictive information than baseline levels. It is not yet established whether baseline or longitudinal amyloid-beta PET measures are associated with a subsequent change in Tau PET measures. Additionally, the pattern of results across anatomic regions, suggests that in this sample Aß burden is associated with the early spread of tau. O1-06-06
IN VIVO TAU-PET INDICATES EXPANSION OF TAU PATHOLOGY WITHIN THE DEFAULT MODE NETWORK IN ALZHEIMER’S DISEASE
Joseph Seemiller1,2, Masoud Tahmasian1, Igor Yakushev3, Alexander Drzezga1, 1University of Cologne, Cologne, Germany; 2The Commonwealth Medical College, Scranton, PA, USA; 3Technische Universit€at M€unchen, Munich, Germany. Contact e-mail: me@ josephseemiller.com Background: Using neuroimaging techniques, striking overlaps between brain regions associated with the default mode functional connectivity network (DMN) and various neurodegenerative pathologies (hypometabolism, amyloid-deposition) have been demonstrated in patients with Alzheimer’s disease (AD). This implies a specific susceptibility of these regions to AD pathology. So far, this type of spatial overlap with the DMN has not yet been systematically explored for tau-deposition in vivo. Methods: The PET-tracer [18F]T807 (AVID Radiopharmaceuticals, Inc.) was used to determine tau deposition in 13 patients with clinically manifest AD (n¼13) and a group of age-matched healthy controls (HC, n¼16). A voxel-wise group comparison (SPM8, unpaired ttest, p<0.001) was performed to obtain a spatial distribution map of significantly increased tracer-uptake in patients as compared to controls. The peak cluster of this tau deposition map was selected as a seed for a functional connectivity map (tau-FC) based on preexisting resting state fMRI images of 198 healthy control subjects. The binarized tau-deposition and tau-FC maps were spatially compared to previously established maps of the DMN and other functional connectivity networks. Results: The voxel-wise group comparison revealed tau deposition bilaterally in the posterior cingulate, parietal, insular, mesial temporal, and frontal cortices in AD patients compared to HC. Visually, the spatial pattern of tau-distribution showed distinct overlap with the DMN (DICE coefficient of 0.62, reflecting 62% similarity of the two patterns). For the tau-FC network (based on the tau-peak), an even greater overlap with the DMN was demonstrated by a DICE coefficient of 0.73. No comparable overlap with other FC-networks was observed. Conclusions: In-vivo tau deposition in AD shows significant overlap with the DMN. The maximum tau-cluster in patients seeds a functional network in healthy subjects that overlaps with the pattern of tau-
BASELINE AMYLOID PET IMAGING, LONGITUDINAL AMYLOID ACCUMULATION, AND TAU PET IMAGING IN PRECLINICAL ALZHEIMER’S DISEASE
Aaron P. Schultz1,2, Elizabeth C. Mormino2,3, Jasmeer P. Chhatwal1,2, Molly LaPoint1, Alex S. Dagley4, Reisa A. Sperling1,2,5, Keith A. Johnson2,4, 1Massachusetts General Hospital and the Athinoula A. Martinos Center for Biomedical Imaging, Boston, MA, USA; 2Harvard Medical School, Boston, MA, USA; 3Massachusetts General Hospital, Boston, MA, USA; 4Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA; 5Brigham and Women’s Hospital, Boston, MA, USA. Contact e-mail: [email protected] Background: Amyloid-beta (Ab) plaque and tau neurofibrillary pa-
thologies both accumulate in cognitively normal elderly individuals and both can now be measured in vivo using PET. We tested whether measures of tau deposition were related to Ab burden or its retrospective 3-year accumulation rate in normal elderly. Methods: Eighty-three participants in the Harvard Aging Brain Study (HABS – P01AG036694; age¼76.166.1; baseline CDR¼0; e4+/e4- 19/56) underwent baseline and followup 11C PiB measurements of Ab over 3.261.2 years (with 2.56.7 visits per subject). Mean cortical PiB DVR and its change with time was compared with inferior temporal 18F T807 SUVR measures of tau We used Freesurfer ROIs, cerebellar grey reference, and the geometric transform metric (GTM) for partial volume correction. Age, gender, and the time between PiB and T807 imaging were included in all models. Results: We found significant relationships between inferior temporal T807 and either baseline PiB (t(78) ¼ 4.38; p<0.001) or rate of accumulation of PiB (t(78) ¼ 2.36; p¼0.008). When both baseline amyloid burden and rate of accumulation were included in the model, baseline amyloid burden re-
P139
mained significant (p<0.001) whereas rate of accumulation did not (p¼0.41). Based on model estimates (not including rate of amyloid accumulation), T807 increases by 0.1860.04 SUVR units for every 1 DVR increase in amyloid relative to a PiB value of 1.41, whereas age (p¼0.025) increases 0.00760.003 SUVR units per year relative to a reference age of 75.8. The same pattern of results held across entorhinal, parahippocampal, fusiform, inferior temporal, middle temporal, and inferior parietal ROIs, but was non-significant for superior temporal, superior parietal, or precuneus. Conclusions: Amyloid-beta and its w3-year accumulation rate are each associated with tau pathologic burden in cognitively normal elderly. However, Aß accumulation rate is low and does not provide stronger predictive information than baseline levels. It is not yet established whether baseline or longitudinal amyloid-beta PET measures are associated with a subsequent change in Tau PET measures. Additionally, the pattern of results across anatomic regions, suggests that in this sample Aß burden is associated with the early spread of tau. O1-06-06
IN VIVO TAU-PET INDICATES EXPANSION OF TAU PATHOLOGY WITHIN THE DEFAULT MODE NETWORK IN ALZHEIMER’S DISEASE
Joseph Seemiller1,2, Masoud Tahmasian1, Igor Yakushev3, Alexander Drzezga1, 1University of Cologne, Cologne, Germany; 2The Commonwealth Medical College, Scranton, PA, USA; 3Technische Universit€at M€unchen, Munich, Germany. Contact e-mail: me@ josephseemiller.com Background: Using neuroimaging techniques, striking overlaps between brain regions associated with the default mode functional connectivity network (DMN) and various neurodegenerative pathologies (hypometabolism, amyloid-deposition) have been demonstrated in patients with Alzheimer’s disease (AD). This implies a specific susceptibility of these regions to AD pathology. So far, this type of spatial overlap with the DMN has not yet been systematically explored for tau-deposition in vivo. Methods: The PET-tracer [18F]T807 (AVID Radiopharmaceuticals, Inc.) was used to determine tau deposition in 13 patients with clinically manifest AD (n¼13) and a group of age-matched healthy controls (HC, n¼16). A voxel-wise group comparison (SPM8, unpaired ttest, p<0.001) was performed to obtain a spatial distribution map of significantly increased tracer-uptake in patients as compared to controls. The peak cluster of this tau deposition map was selected as a seed for a functional connectivity map (tau-FC) based on preexisting resting state fMRI images of 198 healthy control subjects. The binarized tau-deposition and tau-FC maps were spatially compared to previously established maps of the DMN and other functional connectivity networks. Results: The voxel-wise group comparison revealed tau deposition bilaterally in the posterior cingulate, parietal, insular, mesial temporal, and frontal cortices in AD patients compared to HC. Visually, the spatial pattern of tau-distribution showed distinct overlap with the DMN (DICE coefficient of 0.62, reflecting 62% similarity of the two patterns). For the tau-FC network (based on the tau-peak), an even greater overlap with the DMN was demonstrated by a DICE coefficient of 0.73. No comparable overlap with other FC-networks was observed. Conclusions: In-vivo tau deposition in AD shows significant overlap with the DMN. The maximum tau-cluster in patients seeds a functional network in healthy subjects that overlaps with the pattern of tau-