- Email: [email protected]
Kinetic evaluation of three newly developed radioligands for human tau imaging
Developing Topics
voxel-wise. Results: Peak SUV values were approximately 3, 1.5 and 3.5 for [11C]RO6924963, [11C]RO6931643, and [18F] RO6958948, respectively. The retention of [11C]RO6931643 and [18F]RO6958948 in HS was much lower than that of [11C] RO6924963. For [11C]RO6931643 and [18F]RO6958948 (in AD), highest uptake was seen in the frontal (Fr), temporal (Tp), parietal (Pa), occipital (Oc), and fusiform (Fs) cortices, and the entorhinal area (ER). SUVR60-90 values ranged from 1.22 (L. Fr) to 1.55 (L. Oc) for [11C]RO6931643, and 1.39 (R.Fr) to 2.25 (L. Fs) for [18F]RO6958948, and VT ranged from 2.28 (R. ER) to 3.14 (L. Tp), and 3.98 (R. ER) to 5.62 (L. Tp), respectively. Regional analysis of SUVR and VT for [11C]RO6931643 and [18F]RO6958948 clearly allowed AD and HS to be distinguished. When compared to HS, the two tracers showed robust group effects (F>90; p¼<10-6; two-way ANOVA) on SUVR and VT, and significant group differences (p<0.05 with Bonferroni correction; without overlap) in 6 of 12 regions for [11C]RO6931643 and 4 of 12 for [18F]RO6958948 (using SUVR). Voxel-wise analysis of SUVR revealed clusters of significantly higher uptake in AD compared to HS in Fs for [11C]RO6931643 (7 AD vs. 5 HS), and [18F] RO6958948 (5 AD vs. 5 HS). There were no radiolabelled metabolites nor defluorination of [18F]RO6958948. Conclusions: Our data supports further evaluation of [18F]RO6958948. Kinetic analysis is reported in detail in Kuwabara, AAIC 2015.
P4-186
KINETIC EVALUATION OF THREE NEWLY DEVELOPED RADIOLIGANDS FOR HUMAN TAU IMAGING
Hiroto Kuwabara1, Robert A. Comley2, Edilio Borroni2, Michael Honer2, Dean F. Wong1, 1Johns Hopkins University School of Medicine, Baltimore, MD, USA; 2F. Hoffmann-La Roche, Ltd., Basel, Switzerland. Contact e-mail: [email protected] Background: Neuroimaging of aggregated tau may be useful for
monitoring progression of tauopathies such as in Alzheimer’s disease (AD). Three new PET radioligands for tau imaging were evaluated quantitatively in healthy subjects (HS) and patients with AD. Methods: Seven amyloid PET positive AD patients (4M:2F; 67-86 y; MMSE: 16-24), and 7 young HS (5M:2F; 25-38 y) each received 2 different tau tracers. Dynamic 90 min scans were obtained after bolus injection of [11C]RO6924963 (4HS:2AD), [11C]RO6931643 (5HS:7AD), or [18F]RO6958948 (5HS:5AD). Arterial blood sampling was performed in 8/14 AD, and 13/14 HS. Time-activity curves (TAC) were obtained for a total of 41 MRI-derived brain regions. Results: [11C]RO6924963 alone
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showed some regional variation of TACs in HS, and rapid metabolism in plasma (parent fraction: 30% at 5 min; <5% at 90 min). Therefore, only [11C]RO6931643 and [18F]RO6958948 (parent fractions: w30% at 15 min; w10% at 90 min) are reported further. The kinetics of both radioligands can be described by a twotissue compartmental model, and the plots reached asymptotes by 20 min for the plasma-reference graphical analysis (PRGA; Logan et al., 1990) for both groups. Target-cerebellum ratios (¼TRR, a.k.a. SUVR) became stable by 60 min in AD and HS for both radioligands. Regional TRR (¼y) correlated with BPND of PRGA (BPND ¼ target-cerebellum distribution volume ratio less 1) for RO6931643 (y ¼ 0.91∙x + 1.04; R2¼0.963) as well as for RO6958948 (y ¼ 1.8∙x + 1.1; R2¼0.944), using AD data alone. In AD subjects, regional TRR of RO6931643 (n¼7) ranged from 1.22 to 1.55 among high TRR regions including the frontal (Fr), temporal (Tp), parietal (Pa), occipital (Oc), and fusiform (Fs) cortices, and the entorhinal area(ER) (12 regions per side) while TRR of RO6958948 (n¼5) ranged from 1.39 to 2.55. TRR correlated between the two radioligands (RO6958948 ¼ 2∙x 0.96; R2¼0.801; p<10-6). AD subjects showed higher TRR values without overlap in 6/12 regions for RO6931643 and 4/12 regions for RO6958948; p<0.0042 for Bonferroni correction. Conclusions: Of the three candidate radioligands, [11C]RO6931643 and [18F] RO6958948 appeared to be promising radioligands for tau imaging.
P4-187
MIDLIFE ADIPOSITY PREDICTS EARLIER ONSET OF ALZHEIMER’S DEMENTIA, NEUROPATHOLOGY, AND PRESYMPTOMATIC CEREBRAL AMYLOID ACCUMULATION
Madhav Thambisetty1, Yi-Fang Chuang1, Yang An1, Murat Bilgel1, Dean F. Wong2, Juan C. Troncoso2, Richard O’Brien3, John C.S. Breitner4, Susan M. Resnick1, 1National Institute on Aging, Baltimore, MD, USA; 2 Johns Hopkins University School of Medicine, Baltimore, MD, USA; 3Duke University, Durham, NC, USA; 4McGill University Faculty of Medicine, Montreal, QC, Canada. Contact e-mail: [email protected] Background: Understanding how midlife risk factors influence ageat-onset (AAO) of Alzheimer’s disease (AD) may provide clues to delay disease expression. Although midlife adiposity predicts increased incidence of AD, it is unclear whether it affects AAO and severity of Alzheimer’s neuropathology. Methods: Using a prospective population-based cohort, the Baltimore Longitudinal Study of Aging (BLSA), we sought to examine the relationships between midlife body mass index (BMI) and: (1) AAO of AD; (2) severity of Alzheimer’s neuropathology; and (3) fibrillar brain amyloid deposition during aging. We analyzed data from 1,394 cognitively normal individuals at baseline (8643 visits; average follow up interval 13.9 years), 142 of whom developed incident AD. In two sub-samples of BLSA, 191 participants underwent autopsy and neuropathological assessment, and 75 non-demented individuals underwent brain amyloid imaging by 11C-PiB PET. Midlife adiposity was derived from BMI data at 50 years of age. Results: Each unit increase in midlife BMI predicted earlier onset of AD by 6.7 months (P¼0.013). Higher midlife BMI was associated with greater Braak neurofibrillary tangle but not CERAD neuritic plaque scores at autopsy overall. Higher midlife BMI was associated with greater fibrillar amyloid measured by global mean cortical distribution volume ratio and within the precuneus. Conclusions: Midlife overweight predicts earlier onset of AD and
voxel-wise. Results: Peak SUV values were approximately 3, 1.5 and 3.5 for [11C]RO6924963, [11C]RO6931643, and [18F] RO6958948, respectively. The retention of [11C]RO6931643 and [18F]RO6958948 in HS was much lower than that of [11C] RO6924963. For [11C]RO6931643 and [18F]RO6958948 (in AD), highest uptake was seen in the frontal (Fr), temporal (Tp), parietal (Pa), occipital (Oc), and fusiform (Fs) cortices, and the entorhinal area (ER). SUVR60-90 values ranged from 1.22 (L. Fr) to 1.55 (L. Oc) for [11C]RO6931643, and 1.39 (R.Fr) to 2.25 (L. Fs) for [18F]RO6958948, and VT ranged from 2.28 (R. ER) to 3.14 (L. Tp), and 3.98 (R. ER) to 5.62 (L. Tp), respectively. Regional analysis of SUVR and VT for [11C]RO6931643 and [18F]RO6958948 clearly allowed AD and HS to be distinguished. When compared to HS, the two tracers showed robust group effects (F>90; p¼<10-6; two-way ANOVA) on SUVR and VT, and significant group differences (p<0.05 with Bonferroni correction; without overlap) in 6 of 12 regions for [11C]RO6931643 and 4 of 12 for [18F]RO6958948 (using SUVR). Voxel-wise analysis of SUVR revealed clusters of significantly higher uptake in AD compared to HS in Fs for [11C]RO6931643 (7 AD vs. 5 HS), and [18F] RO6958948 (5 AD vs. 5 HS). There were no radiolabelled metabolites nor defluorination of [18F]RO6958948. Conclusions: Our data supports further evaluation of [18F]RO6958948. Kinetic analysis is reported in detail in Kuwabara, AAIC 2015.
P4-186
KINETIC EVALUATION OF THREE NEWLY DEVELOPED RADIOLIGANDS FOR HUMAN TAU IMAGING
Hiroto Kuwabara1, Robert A. Comley2, Edilio Borroni2, Michael Honer2, Dean F. Wong1, 1Johns Hopkins University School of Medicine, Baltimore, MD, USA; 2F. Hoffmann-La Roche, Ltd., Basel, Switzerland. Contact e-mail: [email protected] Background: Neuroimaging of aggregated tau may be useful for
monitoring progression of tauopathies such as in Alzheimer’s disease (AD). Three new PET radioligands for tau imaging were evaluated quantitatively in healthy subjects (HS) and patients with AD. Methods: Seven amyloid PET positive AD patients (4M:2F; 67-86 y; MMSE: 16-24), and 7 young HS (5M:2F; 25-38 y) each received 2 different tau tracers. Dynamic 90 min scans were obtained after bolus injection of [11C]RO6924963 (4HS:2AD), [11C]RO6931643 (5HS:7AD), or [18F]RO6958948 (5HS:5AD). Arterial blood sampling was performed in 8/14 AD, and 13/14 HS. Time-activity curves (TAC) were obtained for a total of 41 MRI-derived brain regions. Results: [11C]RO6924963 alone
P851
showed some regional variation of TACs in HS, and rapid metabolism in plasma (parent fraction: 30% at 5 min; <5% at 90 min). Therefore, only [11C]RO6931643 and [18F]RO6958948 (parent fractions: w30% at 15 min; w10% at 90 min) are reported further. The kinetics of both radioligands can be described by a twotissue compartmental model, and the plots reached asymptotes by 20 min for the plasma-reference graphical analysis (PRGA; Logan et al., 1990) for both groups. Target-cerebellum ratios (¼TRR, a.k.a. SUVR) became stable by 60 min in AD and HS for both radioligands. Regional TRR (¼y) correlated with BPND of PRGA (BPND ¼ target-cerebellum distribution volume ratio less 1) for RO6931643 (y ¼ 0.91∙x + 1.04; R2¼0.963) as well as for RO6958948 (y ¼ 1.8∙x + 1.1; R2¼0.944), using AD data alone. In AD subjects, regional TRR of RO6931643 (n¼7) ranged from 1.22 to 1.55 among high TRR regions including the frontal (Fr), temporal (Tp), parietal (Pa), occipital (Oc), and fusiform (Fs) cortices, and the entorhinal area(ER) (12 regions per side) while TRR of RO6958948 (n¼5) ranged from 1.39 to 2.55. TRR correlated between the two radioligands (RO6958948 ¼ 2∙x 0.96; R2¼0.801; p<10-6). AD subjects showed higher TRR values without overlap in 6/12 regions for RO6931643 and 4/12 regions for RO6958948; p<0.0042 for Bonferroni correction. Conclusions: Of the three candidate radioligands, [11C]RO6931643 and [18F] RO6958948 appeared to be promising radioligands for tau imaging.
P4-187
MIDLIFE ADIPOSITY PREDICTS EARLIER ONSET OF ALZHEIMER’S DEMENTIA, NEUROPATHOLOGY, AND PRESYMPTOMATIC CEREBRAL AMYLOID ACCUMULATION
Madhav Thambisetty1, Yi-Fang Chuang1, Yang An1, Murat Bilgel1, Dean F. Wong2, Juan C. Troncoso2, Richard O’Brien3, John C.S. Breitner4, Susan M. Resnick1, 1National Institute on Aging, Baltimore, MD, USA; 2 Johns Hopkins University School of Medicine, Baltimore, MD, USA; 3Duke University, Durham, NC, USA; 4McGill University Faculty of Medicine, Montreal, QC, Canada. Contact e-mail: [email protected] Background: Understanding how midlife risk factors influence ageat-onset (AAO) of Alzheimer’s disease (AD) may provide clues to delay disease expression. Although midlife adiposity predicts increased incidence of AD, it is unclear whether it affects AAO and severity of Alzheimer’s neuropathology. Methods: Using a prospective population-based cohort, the Baltimore Longitudinal Study of Aging (BLSA), we sought to examine the relationships between midlife body mass index (BMI) and: (1) AAO of AD; (2) severity of Alzheimer’s neuropathology; and (3) fibrillar brain amyloid deposition during aging. We analyzed data from 1,394 cognitively normal individuals at baseline (8643 visits; average follow up interval 13.9 years), 142 of whom developed incident AD. In two sub-samples of BLSA, 191 participants underwent autopsy and neuropathological assessment, and 75 non-demented individuals underwent brain amyloid imaging by 11C-PiB PET. Midlife adiposity was derived from BMI data at 50 years of age. Results: Each unit increase in midlife BMI predicted earlier onset of AD by 6.7 months (P¼0.013). Higher midlife BMI was associated with greater Braak neurofibrillary tangle but not CERAD neuritic plaque scores at autopsy overall. Higher midlife BMI was associated with greater fibrillar amyloid measured by global mean cortical distribution volume ratio and within the precuneus. Conclusions: Midlife overweight predicts earlier onset of AD and