- Email: [email protected]
Associations of [18F]AV1451 Tau PET with age, ApoE genotype, and cognition in Alzheimer’s disease
Poster Presentations: IC-P IC-P-156
P105
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 and 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 pathologies 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 remained 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 w3year 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. IC-P-157
Figure 1. [18F]AV1451 Retention in 12 patients with AD clinical variants
Gothenburg, Sweden; 6Lawrence Berkeley National Laboratory, Berkeley, CA, USA. Contact e-mail: [email protected] Background: Differential patterns of neurofibrillary tangles at au-
topsy are associated with age-at-onset, ApoE-ε4 carrier status, and cognitive profiles in Alzheimer’s disease (AD). We explored relationships between these factors and the in vivo distribution of the novel tau-PET tracer [18F]AV1451 in a heterogeneous population of AD subjects. Methods: [18F]AV1451-PET was performed in 12 patients with probable AD dementia (NIA-AA; 5 with visuospatial-predominant clinical presentation, 4 with language-predominant presentation, 3 with memory-predominant presentation; Table 1). We created 80-100 minute SUVr images normalized by cerebellar grey (Figure 1). Voxelwise regressions between [18F] AV1451 retention and (separately) age, ApoE-ε4 carrier status (+/-), and MMSE were performed in SPM8. Additional models compared performance on 3 cognitive tasks (modified trailmaking, figure copy, and figure recall) against voxelwise SUVr after adjusting for MMSE. Given the small sample size and explorative nature of this study, we applied a liberal statistical threshold (p<0.05 uncorrected, k¼50). Results: Voxelwise regression showed that older age was associated with increased hippocampal [18F]AV1451 uptake, while younger age correlated with increased uptake throughout association cortex (Figure 2), mirroring previously
ASSOCIATIONS OF [18F]AV1451 TAU PET WITH AGE, APOE GENOTYPE, AND COGNITION IN ALZHEIMER’S DISEASE
Daniel Schonhaut1, Rik Ossenkoppele1,2,3, Michael Sch€oll4,5, Sam Lockhart4, Suzanne Baker4, Andreas Lazaris1, Averill Cantwell1, Jacob W. Vogel4, Nagehan Ayakta1, Marilu Gorno-Tempini1, Zachary A. Miller1, James P. O’Neil6, Bruce L. Miller1, William J. Jagust4,6, Gil D. Rabinovici1, 1University of California San Francisco, San Francisco, CA, USA; 2VU University Medical Center, Amsterdam, Netherlands; 3 Neuroscience Campus Amsterdam, Amsterdam, Netherlands; 4University of California Berkeley, Berkeley, CA, USA; 5University of Gothenburg,
Figure 2. [18F]AV1451 associations with age, ApoE-ε4 +, and MMSE
P106
Poster Presentations: IC-P IC-P-158
A MULTISCALE MRI APPROACH TO INVESTIGATE NOVEL DRUG TREATMENT STRATEGIES IN MOUSE MODELS OF ALZHEIMER’S DISEASE
Ozama Ismail1, Holly Holmes1, Niall Colgan1, Da Ma1, Jack A. Wells1, Nicholas M. Powell1, James M. O’Callaghan1, Ian F. Harrison1, Simon Walker-Samuel1, Jorge M. Cardoso1, Marc Modat1, Elizabeth Fisher1, Sebastien Ourselin2, Tracey K. Murray3, Zeshan Ahmed3, Michael J. O’Neill3, Ross A. Johnson4, Emily C. Collins4, Mark F. Lythgoe1, 1University College London, London, United Kingdom; 2 Centre for Medical Image Computing, University College London, London, United Kingdom; 3Eli Lilly and Company, Surrey, United Kingdom; 4Eli Lilly and Company, Indianapolis, IN, USA. Contact e-mail: o.ismail@ucl. ac.uk Background: Several emerging therapies focus on preventing and 18
Figure 3. Increased [ F]AV1451 retention with visuospatial/memory task deficits
described effects of age on clinical presentation (greater memory impairment in older patients, diffuse cortical deficits in younger patients) and neurodegenerative patterns (medial temporal in lateonset AD and cortical-predominant in early-onset AD). ApoE-ε4 carriers had greater right-parietal and bilateral lateral-temporal retention than non-carriers. Lower MMSE scores predicted greater uptake in inferior/middle frontal gyri and left-temporal pole, consistent with spread of tau into anterior brain regions with advancing disease. These results remained largely unchanged when age, ApoE-ε4 and MMSE were included in a combined model. Decreased performance on modified trailmaking, figure copy, and figure recall tasks was related to increased uptake in right-occipitoparietal visual association cortex, and impaired figure recall also predicted tracer retention in right>left hippocampus (Figure 3). Conclusions: We found preliminary associations between [18F]AV1451 binding patterns and age, ApoE-ε4 and domain-specific cognitive performance, mirroring links between these factors and the distribution of neurofibrillary tangles at autopsy. These findings need to be confirmed in larger samples.
Table 1 Demographics, cognitive testing, and regional SUVr means. AD Patients N Cognitive Presentation Age Sex (M/F) ApoE ε4 Carrier (Y/N) Cognitive Testing MMSE Modified Trails Per Min Benson Figure Copy Benson Figure Memory [18F]AV1451 SUVr Global Frontal Lateral Temporal Medial Temporal Parietal Occipital
clearing the accumulation of pathological lesions of tau in Alzheimer’s disease. As such, there is high demand for early biomarkers sensitive to tau pathology in vivo. To assess the sensitivity of MRI to tau suppression, we longitudinally imaged two cohorts of rTg4510 mice, with doxycycline administered from 3.5 months (‘early’ intervention) and 4.5 months (‘late’ intervention) to coincide with the development of pathological tau products within the forebrain from 2.5 months. We investigated the exchange of endogenous mobile proteins using amide proton transfer(APT), microstructural diffusion using diffusion tensor imaging(DTI) and morphometric changes using high-resolution structural MRI. Methods: 39 rTg4510, and 18 wildtype (WT) litter-matched mice were scanned at baseline (3.5 months for the ‘early’ intervention study and 4.5 months for the ‘late’ intervention study) for APT, DTI and structural imaging using a 9.4T MRI and parameters previously described. 10 rTg4510 from each cohort were then treated with doxycycline hyclate(10mg/kg) and maintained on a doxycycline diet for the remainder of the study to supress tau-expression. The doxycycline-treated rTg4510s, untreated rTg4510s and WTs were imaged again at 5.5 and 7.5 months for APT, DTI and structural imaging. Results: Atrophy was detectable in rTg4510s from 5.5 months (Fig.1A). Volume loss was lower in animals treated with doxycycline from 3.5 months than in those treated from 4.5 months. Both interventions produced an increase in APT towards WT values by 7.5 months (Fig.1B,E). Following early treatment (3.5 months), APT within the treated rTg4510s remained within the range of WTs until 7.5 months (Fig.1B). Here, both the treated rTg4510s and the WTs were significantly greater than untreated rTg4510s. DTI discriminated
12 5 visuospatial, 4 language, 3 memory 64.2 (8.6), range: 52 – 75 3/9 5/5 (2 unknown) 21.5(6.0), range: 8 – 29 8.2(9.9), range: 0.5 – 29.0 8.7(5.8), range: 1 – 16 3.9(3.7), range: 0 – 11 1.9(0.4), range: 1.6 – 2.8 1.6(0.5), range: 1.2 – 2.8 2.2(0.5), range: 1.7 – 3.1 1.5(0.2), range: 1.1 – 1.9 2.3(0.6), range: 1.7 – 3.4 1.9(0.4), range: 1.3 – 2.6
Figure 1. Multiparametric MRI results following early (A-C) and late (D-F) therapeutic intervention. Results are shown for the high tau pathology regions. Error bars represent the standard error of the mean. WT vs. rTg4510: * ¼ p 0.05; ** ¼ p0.01; *** ¼ p 0.001; **** ¼ p 0.001. WT vs. rTg4510(+DOX); þ ¼ p 0.05; ++++ ¼ p 0.0001. rTg4510s. vs. rTg4510(+DOX); – ¼ p 0.01; —— ¼ p 0.0001.
P105
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 and 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 pathologies 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 remained 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 w3year 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. IC-P-157
Figure 1. [18F]AV1451 Retention in 12 patients with AD clinical variants
Gothenburg, Sweden; 6Lawrence Berkeley National Laboratory, Berkeley, CA, USA. Contact e-mail: [email protected] Background: Differential patterns of neurofibrillary tangles at au-
topsy are associated with age-at-onset, ApoE-ε4 carrier status, and cognitive profiles in Alzheimer’s disease (AD). We explored relationships between these factors and the in vivo distribution of the novel tau-PET tracer [18F]AV1451 in a heterogeneous population of AD subjects. Methods: [18F]AV1451-PET was performed in 12 patients with probable AD dementia (NIA-AA; 5 with visuospatial-predominant clinical presentation, 4 with language-predominant presentation, 3 with memory-predominant presentation; Table 1). We created 80-100 minute SUVr images normalized by cerebellar grey (Figure 1). Voxelwise regressions between [18F] AV1451 retention and (separately) age, ApoE-ε4 carrier status (+/-), and MMSE were performed in SPM8. Additional models compared performance on 3 cognitive tasks (modified trailmaking, figure copy, and figure recall) against voxelwise SUVr after adjusting for MMSE. Given the small sample size and explorative nature of this study, we applied a liberal statistical threshold (p<0.05 uncorrected, k¼50). Results: Voxelwise regression showed that older age was associated with increased hippocampal [18F]AV1451 uptake, while younger age correlated with increased uptake throughout association cortex (Figure 2), mirroring previously
ASSOCIATIONS OF [18F]AV1451 TAU PET WITH AGE, APOE GENOTYPE, AND COGNITION IN ALZHEIMER’S DISEASE
Daniel Schonhaut1, Rik Ossenkoppele1,2,3, Michael Sch€oll4,5, Sam Lockhart4, Suzanne Baker4, Andreas Lazaris1, Averill Cantwell1, Jacob W. Vogel4, Nagehan Ayakta1, Marilu Gorno-Tempini1, Zachary A. Miller1, James P. O’Neil6, Bruce L. Miller1, William J. Jagust4,6, Gil D. Rabinovici1, 1University of California San Francisco, San Francisco, CA, USA; 2VU University Medical Center, Amsterdam, Netherlands; 3 Neuroscience Campus Amsterdam, Amsterdam, Netherlands; 4University of California Berkeley, Berkeley, CA, USA; 5University of Gothenburg,
Figure 2. [18F]AV1451 associations with age, ApoE-ε4 +, and MMSE
P106
Poster Presentations: IC-P IC-P-158
A MULTISCALE MRI APPROACH TO INVESTIGATE NOVEL DRUG TREATMENT STRATEGIES IN MOUSE MODELS OF ALZHEIMER’S DISEASE
Ozama Ismail1, Holly Holmes1, Niall Colgan1, Da Ma1, Jack A. Wells1, Nicholas M. Powell1, James M. O’Callaghan1, Ian F. Harrison1, Simon Walker-Samuel1, Jorge M. Cardoso1, Marc Modat1, Elizabeth Fisher1, Sebastien Ourselin2, Tracey K. Murray3, Zeshan Ahmed3, Michael J. O’Neill3, Ross A. Johnson4, Emily C. Collins4, Mark F. Lythgoe1, 1University College London, London, United Kingdom; 2 Centre for Medical Image Computing, University College London, London, United Kingdom; 3Eli Lilly and Company, Surrey, United Kingdom; 4Eli Lilly and Company, Indianapolis, IN, USA. Contact e-mail: o.ismail@ucl. ac.uk Background: Several emerging therapies focus on preventing and 18
Figure 3. Increased [ F]AV1451 retention with visuospatial/memory task deficits
described effects of age on clinical presentation (greater memory impairment in older patients, diffuse cortical deficits in younger patients) and neurodegenerative patterns (medial temporal in lateonset AD and cortical-predominant in early-onset AD). ApoE-ε4 carriers had greater right-parietal and bilateral lateral-temporal retention than non-carriers. Lower MMSE scores predicted greater uptake in inferior/middle frontal gyri and left-temporal pole, consistent with spread of tau into anterior brain regions with advancing disease. These results remained largely unchanged when age, ApoE-ε4 and MMSE were included in a combined model. Decreased performance on modified trailmaking, figure copy, and figure recall tasks was related to increased uptake in right-occipitoparietal visual association cortex, and impaired figure recall also predicted tracer retention in right>left hippocampus (Figure 3). Conclusions: We found preliminary associations between [18F]AV1451 binding patterns and age, ApoE-ε4 and domain-specific cognitive performance, mirroring links between these factors and the distribution of neurofibrillary tangles at autopsy. These findings need to be confirmed in larger samples.
Table 1 Demographics, cognitive testing, and regional SUVr means. AD Patients N Cognitive Presentation Age Sex (M/F) ApoE ε4 Carrier (Y/N) Cognitive Testing MMSE Modified Trails Per Min Benson Figure Copy Benson Figure Memory [18F]AV1451 SUVr Global Frontal Lateral Temporal Medial Temporal Parietal Occipital
clearing the accumulation of pathological lesions of tau in Alzheimer’s disease. As such, there is high demand for early biomarkers sensitive to tau pathology in vivo. To assess the sensitivity of MRI to tau suppression, we longitudinally imaged two cohorts of rTg4510 mice, with doxycycline administered from 3.5 months (‘early’ intervention) and 4.5 months (‘late’ intervention) to coincide with the development of pathological tau products within the forebrain from 2.5 months. We investigated the exchange of endogenous mobile proteins using amide proton transfer(APT), microstructural diffusion using diffusion tensor imaging(DTI) and morphometric changes using high-resolution structural MRI. Methods: 39 rTg4510, and 18 wildtype (WT) litter-matched mice were scanned at baseline (3.5 months for the ‘early’ intervention study and 4.5 months for the ‘late’ intervention study) for APT, DTI and structural imaging using a 9.4T MRI and parameters previously described. 10 rTg4510 from each cohort were then treated with doxycycline hyclate(10mg/kg) and maintained on a doxycycline diet for the remainder of the study to supress tau-expression. The doxycycline-treated rTg4510s, untreated rTg4510s and WTs were imaged again at 5.5 and 7.5 months for APT, DTI and structural imaging. Results: Atrophy was detectable in rTg4510s from 5.5 months (Fig.1A). Volume loss was lower in animals treated with doxycycline from 3.5 months than in those treated from 4.5 months. Both interventions produced an increase in APT towards WT values by 7.5 months (Fig.1B,E). Following early treatment (3.5 months), APT within the treated rTg4510s remained within the range of WTs until 7.5 months (Fig.1B). Here, both the treated rTg4510s and the WTs were significantly greater than untreated rTg4510s. DTI discriminated
12 5 visuospatial, 4 language, 3 memory 64.2 (8.6), range: 52 – 75 3/9 5/5 (2 unknown) 21.5(6.0), range: 8 – 29 8.2(9.9), range: 0.5 – 29.0 8.7(5.8), range: 1 – 16 3.9(3.7), range: 0 – 11 1.9(0.4), range: 1.6 – 2.8 1.6(0.5), range: 1.2 – 2.8 2.2(0.5), range: 1.7 – 3.1 1.5(0.2), range: 1.1 – 1.9 2.3(0.6), range: 1.7 – 3.4 1.9(0.4), range: 1.3 – 2.6
Figure 1. Multiparametric MRI results following early (A-C) and late (D-F) therapeutic intervention. Results are shown for the high tau pathology regions. Error bars represent the standard error of the mean. WT vs. rTg4510: * ¼ p 0.05; ** ¼ p0.01; *** ¼ p 0.001; **** ¼ p 0.001. WT vs. rTg4510(+DOX); þ ¼ p 0.05; ++++ ¼ p 0.0001. rTg4510s. vs. rTg4510(+DOX); – ¼ p 0.01; —— ¼ p 0.0001.