- Email: [email protected]
Longitudinal volumetric MRI analysis for use in Alzheimer's disease multi-site clinical trials: Comparison to analysis methods used in ADNI and correlation to MMSE change
S6
Alzheimer’s Imaging Consortium IC-P: Imaging Posters
and no distal cues, or (2) hippocampal-based spatial MWM with hidden platform and distal visual cues. Performance was assessed using escape latencies and probe trial parameters. Ten days post-training, mice were transcardially perfused. Brains within intact skulls were post-fixed and imaged using highresolution (32 micron isotropic) T2-weighted MRI at 7T. Deformation-based morphometry (DBM) was used to identify focal volume changes correlated with cognitive task performance using a general linear model (Lerch et al, 2008). Results: All mice undergoing the non-spatial MWM performed equally well. Focal volume increase associated with non-spatial MWM was observed in the striatum. On spatial MWM, APP mice displayed significantly prolonged escape latencies to reach the hidden platform compared to WT. Pioglitazone-treated APP mice exhibited a trend for reduced latencies during training, and a slightly higher number of platform-crossings than untreated APP mice during probe trial. Focal volume increase associated with spatial MWM performance was observed in the hippocampus in WT mice and treated APP mice, but not in untreated APP mice. Conclusions: We have demonstrated using high resolution MRI and DBM that spatial learning-induced hippocampal brain plasticity is absent in young APP mice. Pioglitazone-treatment in young APP mice had beneficial effects on focal hippocampal volume growth associated with spatial MWM performance, and completely rescued cerebrovascular function, suggesting that early and continued pioglitazone treatment may slow AD progression.
IC-P-002
PET IMAGING OF ALZHEIMER’S DISEASE (AD) TRANSGENIC MICE WITH F-18 LABELED 8-HYDROXY QUINOLINE
Padmakar V. Kulkarni1, Neil Vasdev2, Veera Arora1, Guiang Hao1, Michael Long1, Nikolai Slavine1, Bao-Xi Qu1, Xiankai Sun1, Michael Bennett1, Peter P. Antich1, Frederick J. Bonte1, 1The University of Texas Southwestern Medical Center, Dallas, TX, USA; 2CAMH, University of Toronto, Toronto, ON, Canada. Contact e-mail: padmakar.kulkarni@ utsouthwestern.edu Background: Elevated levels of transition metal ions (Cu2+ and Zn2+) in Amyloid plaques are potential targets. Weak metal chelator, hydroxyquinoline (HQ) derivatives are under investigation for therapeutic and diagnostic applications. Radioiodinated clioquinol has been used as a biomarker for b-amyloid, however, it had very low brain uptake. Thus, [123/124I]CQ might not be ideal for diagnostic imaging. A small, blood brain barrier (BBB) permeating, 18F-labeled HQ could be useful for imaging amyloid plaques. Methods: 8-benzyloxy-2-chloroquinoline was reacted with [K222] [18F] in DMSO at 135 C followed by catalytic hydrogenation. The product was formulated with saline after HPLC purification in an overall synthesis time of 70 min (30% uncorrected radiochemical yield: specific activity >1 Ci/mmol). Control (B6) and Tg mice (APPswe, PSEN1dE9), age 12 months, n ¼ 3, were imaged in a Siemens InveonÒ PET-CT scanner. Image acquisition was started immediately after i.v. injection of the tracer (50-90 mCi) and continued up to 30 min. Mice brain sections were stained with polyclonal anti-Ab-42 antibody. Results: PET images showed high (8-10 %ID/g) and fast (1 min) uptake in mice brains and rapid washout of the tracer from the control mice brains while Tg mice had delayed washout. Activity in the brain as a function of time was expressed as a sum of two exponential functions with different slopes: f (t) ¼ A1 * exp (-B1*t) + A2 * exp (-B2*t), where A1, A2, B1, B2 are fitting coefficients and were different (except for A1) for control (A1 ¼ 104, A2 ¼ 20.4, B1 ¼ 1.32, B2 ¼ 0.031) and AD (A1 ¼ 104, A2 ¼ 51, B1 ¼ 1.46, B2 ¼ 0.023) mice. Brain uptake (ID/g) ratio (AD/control) rapidly increased from 1.1 at one minute to 2.2 at 10 minutes post injection and reached 2.6 at 30 min. Brain uptake ratio (Y) vs. time (X) was expressed by the equation Y ¼ 1.36+0.36 * ln (X) indicating persistent increase with time. Conclusions: PET/CT images showed discrete distribution of F-18 labeled HQ in AD mice brains and delayed washout, whereas it rapidly washed out from control mice brains. Immunohistologic staining confirmed the presence of plaques in AD mice brain. F-18 labeled HQ derivatives appear to be promising molecules and warrant further evaluation of this class of molecules as plaque imaging agents.
IC-P-003
LONGITUDINAL VOLUMETRIC MRI ANALYSIS FOR USE IN ALZHEIMER’S DISEASE MULTI-SITE CLINICAL TRIALS: COMPARISON TO ANALYSIS METHODS USED IN ADNI AND CORRELATION TO MMSE CHANGE
Katherine Chong, Wan Chi Lau, Jason Leong, Joyce Suhy, Joonmi Oh, Synarc Inc., San Francisco, CA, USA. Contact e-mail: katherine.chong@ synarc.com Background: The aim of this study was to validate the Synarc in-house analysis methods that quantify cerebral atrophy using the Alzheimer’s Disease Neuroimaging Initiative (ADNI) data set. Imaging biomarkers included in this study were whole brain atrophy (WBA), ventricular enlargement (VE) and hippocampus volume (HV) measurement. Methods: A sample of 101 subjects from the ADNI database was used (48 AD, 29 MCI, and 24 normal controls). The WBA, VE and HV were compared to the analysis results from two academic research groups from the same subjects: differential bias correction-brain boundary shift integral (DBC-BBSI) and ventricular-BSI (VBSI) from the Dementia Research Centre (DRC), and cross-sectional FreeSurfer based hippocampus volume (HV-FS) from the Center for Imaging of Neurodegenerative Disease (CIND). Standard least square mean (LSM) tests were used for sub-group comparisons. The standard method to calculate sample sizes that give 80% power and 5% significance level to detect 25% treatment effect were used. Non-parametric Spearman method was used for a correlation test. The results were reported as mean (standard deviation) unless otherwise noted. In this study, p < 0.05 was regarded as significant. Results: The annualized rate changes for WBA (0.9 (1.0) %), VE (7.9 (9.3) %) and HV (3.1 (2.9) %) were statistically equivalent to DBC-BBSI (1.1 (1.0) %, P ¼ 0.107), VBSI (7.7 (7.9) %, P ¼ 0.827), and HV-FS (3.0 (3.7) %, P ¼ 0.844), respectively, for all subjects. The LSMs for WBA (1.4 (0.1) %), VE (10.8 (1.3) %) and HV (4.2 (0.4) %) in AD were significantly higher than in controls (0.2 (0.2) %, 3.5 (1.8) %, 1.5 (0.6) %, respectively). The required sample sizes using WBA, VE and HV were 88, 77 and 143, respectively. Lastly, all imaging biomarkers correlated moderately with change in MMSE score. Conclusions: We conclude that WBA, VE and HV rates of change from our institute are not significantly different than those from the DRC and CIND, respectively. We also observed that the measured WBA, VE and HV rate changes were significantly higher in AD subjects relative to the normal control group, showing that our methods were sensitive enough to detect changes in subjects with AD.
IC-P-004
IN-VITRO CELLULAR UPTAKE OF A MAGNETIC RESONANCE IMAGING (MRI)/FLUORESCENT CONTRAST AGENT FOR DETECTION OF CATHEPSIN-D ACTIVITY IN ALZHEIMER’S DISEASE
Robert M. Ta1,2, Alex X. Li1, Mojmir Suchy1,3, Robert H. E. Hudson3, Stephen H. Pasternak4,5, Robert Bartha1,2, 1Imaging Research Group, Robarts Research Institute, London, ON, Canada; 2Department of Medical Biophysics, University of Western Ontario, London, ON, Canada; 3 Department of Chemistry, University of Western Ontario, London, ON, Canada; 4Molecular Brain Research Group, Robarts Research Institute, London, ON, Canada; 5Department of Clinical Neurological Sciences, University of Western Ontario, London, ON, Canada. Contact e-mail: rta@ imaging.robarts.ca Background: There are currently no clinically useful biomarkers for the early diagnosis of Alzheimer’s disease (AD). Cathepsin D (CatD) is a lysosomal protease present at elevated levels in amyloid plaques and neuronal cells of AD patients. We have synthesized a magnetic resonance imaging (MRI)/fluorescent contrast agent, DOTA-CAT, to detect CatD. DOTA-CAT consists of a DOTA-caged metal ion, coupled to a cell-penetrating peptide sequence and a CatD recognition site. A fluorescent probe, Oregon Green, was also attached to DOTA-CAT to monitor its uptake optically. The purpose of this study was to establish the cellular
Alzheimer’s Imaging Consortium IC-P: Imaging Posters
and no distal cues, or (2) hippocampal-based spatial MWM with hidden platform and distal visual cues. Performance was assessed using escape latencies and probe trial parameters. Ten days post-training, mice were transcardially perfused. Brains within intact skulls were post-fixed and imaged using highresolution (32 micron isotropic) T2-weighted MRI at 7T. Deformation-based morphometry (DBM) was used to identify focal volume changes correlated with cognitive task performance using a general linear model (Lerch et al, 2008). Results: All mice undergoing the non-spatial MWM performed equally well. Focal volume increase associated with non-spatial MWM was observed in the striatum. On spatial MWM, APP mice displayed significantly prolonged escape latencies to reach the hidden platform compared to WT. Pioglitazone-treated APP mice exhibited a trend for reduced latencies during training, and a slightly higher number of platform-crossings than untreated APP mice during probe trial. Focal volume increase associated with spatial MWM performance was observed in the hippocampus in WT mice and treated APP mice, but not in untreated APP mice. Conclusions: We have demonstrated using high resolution MRI and DBM that spatial learning-induced hippocampal brain plasticity is absent in young APP mice. Pioglitazone-treatment in young APP mice had beneficial effects on focal hippocampal volume growth associated with spatial MWM performance, and completely rescued cerebrovascular function, suggesting that early and continued pioglitazone treatment may slow AD progression.
IC-P-002
PET IMAGING OF ALZHEIMER’S DISEASE (AD) TRANSGENIC MICE WITH F-18 LABELED 8-HYDROXY QUINOLINE
Padmakar V. Kulkarni1, Neil Vasdev2, Veera Arora1, Guiang Hao1, Michael Long1, Nikolai Slavine1, Bao-Xi Qu1, Xiankai Sun1, Michael Bennett1, Peter P. Antich1, Frederick J. Bonte1, 1The University of Texas Southwestern Medical Center, Dallas, TX, USA; 2CAMH, University of Toronto, Toronto, ON, Canada. Contact e-mail: padmakar.kulkarni@ utsouthwestern.edu Background: Elevated levels of transition metal ions (Cu2+ and Zn2+) in Amyloid plaques are potential targets. Weak metal chelator, hydroxyquinoline (HQ) derivatives are under investigation for therapeutic and diagnostic applications. Radioiodinated clioquinol has been used as a biomarker for b-amyloid, however, it had very low brain uptake. Thus, [123/124I]CQ might not be ideal for diagnostic imaging. A small, blood brain barrier (BBB) permeating, 18F-labeled HQ could be useful for imaging amyloid plaques. Methods: 8-benzyloxy-2-chloroquinoline was reacted with [K222] [18F] in DMSO at 135 C followed by catalytic hydrogenation. The product was formulated with saline after HPLC purification in an overall synthesis time of 70 min (30% uncorrected radiochemical yield: specific activity >1 Ci/mmol). Control (B6) and Tg mice (APPswe, PSEN1dE9), age 12 months, n ¼ 3, were imaged in a Siemens InveonÒ PET-CT scanner. Image acquisition was started immediately after i.v. injection of the tracer (50-90 mCi) and continued up to 30 min. Mice brain sections were stained with polyclonal anti-Ab-42 antibody. Results: PET images showed high (8-10 %ID/g) and fast (1 min) uptake in mice brains and rapid washout of the tracer from the control mice brains while Tg mice had delayed washout. Activity in the brain as a function of time was expressed as a sum of two exponential functions with different slopes: f (t) ¼ A1 * exp (-B1*t) + A2 * exp (-B2*t), where A1, A2, B1, B2 are fitting coefficients and were different (except for A1) for control (A1 ¼ 104, A2 ¼ 20.4, B1 ¼ 1.32, B2 ¼ 0.031) and AD (A1 ¼ 104, A2 ¼ 51, B1 ¼ 1.46, B2 ¼ 0.023) mice. Brain uptake (ID/g) ratio (AD/control) rapidly increased from 1.1 at one minute to 2.2 at 10 minutes post injection and reached 2.6 at 30 min. Brain uptake ratio (Y) vs. time (X) was expressed by the equation Y ¼ 1.36+0.36 * ln (X) indicating persistent increase with time. Conclusions: PET/CT images showed discrete distribution of F-18 labeled HQ in AD mice brains and delayed washout, whereas it rapidly washed out from control mice brains. Immunohistologic staining confirmed the presence of plaques in AD mice brain. F-18 labeled HQ derivatives appear to be promising molecules and warrant further evaluation of this class of molecules as plaque imaging agents.
IC-P-003
LONGITUDINAL VOLUMETRIC MRI ANALYSIS FOR USE IN ALZHEIMER’S DISEASE MULTI-SITE CLINICAL TRIALS: COMPARISON TO ANALYSIS METHODS USED IN ADNI AND CORRELATION TO MMSE CHANGE
Katherine Chong, Wan Chi Lau, Jason Leong, Joyce Suhy, Joonmi Oh, Synarc Inc., San Francisco, CA, USA. Contact e-mail: katherine.chong@ synarc.com Background: The aim of this study was to validate the Synarc in-house analysis methods that quantify cerebral atrophy using the Alzheimer’s Disease Neuroimaging Initiative (ADNI) data set. Imaging biomarkers included in this study were whole brain atrophy (WBA), ventricular enlargement (VE) and hippocampus volume (HV) measurement. Methods: A sample of 101 subjects from the ADNI database was used (48 AD, 29 MCI, and 24 normal controls). The WBA, VE and HV were compared to the analysis results from two academic research groups from the same subjects: differential bias correction-brain boundary shift integral (DBC-BBSI) and ventricular-BSI (VBSI) from the Dementia Research Centre (DRC), and cross-sectional FreeSurfer based hippocampus volume (HV-FS) from the Center for Imaging of Neurodegenerative Disease (CIND). Standard least square mean (LSM) tests were used for sub-group comparisons. The standard method to calculate sample sizes that give 80% power and 5% significance level to detect 25% treatment effect were used. Non-parametric Spearman method was used for a correlation test. The results were reported as mean (standard deviation) unless otherwise noted. In this study, p < 0.05 was regarded as significant. Results: The annualized rate changes for WBA (0.9 (1.0) %), VE (7.9 (9.3) %) and HV (3.1 (2.9) %) were statistically equivalent to DBC-BBSI (1.1 (1.0) %, P ¼ 0.107), VBSI (7.7 (7.9) %, P ¼ 0.827), and HV-FS (3.0 (3.7) %, P ¼ 0.844), respectively, for all subjects. The LSMs for WBA (1.4 (0.1) %), VE (10.8 (1.3) %) and HV (4.2 (0.4) %) in AD were significantly higher than in controls (0.2 (0.2) %, 3.5 (1.8) %, 1.5 (0.6) %, respectively). The required sample sizes using WBA, VE and HV were 88, 77 and 143, respectively. Lastly, all imaging biomarkers correlated moderately with change in MMSE score. Conclusions: We conclude that WBA, VE and HV rates of change from our institute are not significantly different than those from the DRC and CIND, respectively. We also observed that the measured WBA, VE and HV rate changes were significantly higher in AD subjects relative to the normal control group, showing that our methods were sensitive enough to detect changes in subjects with AD.
IC-P-004
IN-VITRO CELLULAR UPTAKE OF A MAGNETIC RESONANCE IMAGING (MRI)/FLUORESCENT CONTRAST AGENT FOR DETECTION OF CATHEPSIN-D ACTIVITY IN ALZHEIMER’S DISEASE
Robert M. Ta1,2, Alex X. Li1, Mojmir Suchy1,3, Robert H. E. Hudson3, Stephen H. Pasternak4,5, Robert Bartha1,2, 1Imaging Research Group, Robarts Research Institute, London, ON, Canada; 2Department of Medical Biophysics, University of Western Ontario, London, ON, Canada; 3 Department of Chemistry, University of Western Ontario, London, ON, Canada; 4Molecular Brain Research Group, Robarts Research Institute, London, ON, Canada; 5Department of Clinical Neurological Sciences, University of Western Ontario, London, ON, Canada. Contact e-mail: rta@ imaging.robarts.ca Background: There are currently no clinically useful biomarkers for the early diagnosis of Alzheimer’s disease (AD). Cathepsin D (CatD) is a lysosomal protease present at elevated levels in amyloid plaques and neuronal cells of AD patients. We have synthesized a magnetic resonance imaging (MRI)/fluorescent contrast agent, DOTA-CAT, to detect CatD. DOTA-CAT consists of a DOTA-caged metal ion, coupled to a cell-penetrating peptide sequence and a CatD recognition site. A fluorescent probe, Oregon Green, was also attached to DOTA-CAT to monitor its uptake optically. The purpose of this study was to establish the cellular