Browsing by Subject "Pittsburgh compound B"

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    Comparing amyloid-β plaque burden with antemortem PiB PET in autosomal dominant and late-onset Alzheimer disease
    (Springer, 2021) Chen, Charles D.; Joseph-Mathurin, Nelly; Sinha, Namita; Zhou, Aihong; Li, Yan; Friedrichsen, Karl; McCullough, Austin; Franklin, Erin E.; Hornbeck, Russ; Gordon, Brian; Sharma, Vijay; Cruchaga, Carlos; Goate, Alison; Karch, Celeste; McDade, Eric; Xiong, Chengjie; Bateman, Randall J.; Ghetti, Bernardino; Ringman, John M.; Chhatwal, Jasmeer; Masters, Colin L.; McLean, Catriona; Lashley, Tammaryn; Su, Yi; Koeppe, Robert; Jack, Clifford; Klunk, William E.; Morris, John C.; Perrin, Richard J.; Cairns, Nigel J.; Benzinger, Tammie L.S.; Pathology and Laboratory Medicine, School of Medicine
    Pittsburgh compound B (PiB) radiotracer for positron emission tomography (PET) imaging can bind to different types of amyloid-β plaques and blood vessels (cerebral amyloid angiopathy). However, the relative contributions of different plaque subtypes (diffuse versus cored/compact) to in vivo PiB PET signal on a region-by-region basis is incompletely understood. Of particular interest is whether the same staging schemes for summarizing amyloid-β burden are appropriate for both late-onset and autosomal dominant forms of Alzheimer disease (LOAD and ADAD). Here we compared antemortem PiB PET with follow-up postmortem estimation of amyloid-β burden using stereologic methods to estimate the relative area fraction of diffuse and cored/compact amyloid-β plaques across 16 brain regions in 15 individuals with ADAD and 14 individuals with LOAD. In ADAD, we found that PiB PET correlated with diffuse plaques in the frontal, parietal, temporal, and striatal regions commonly used to summarize amyloid-β burden in PiB PET, and correlated with both diffuse and cored/compact plaques in the occipital lobe and parahippocampal gyrus. In LOAD, we found that PiB PET correlated with both diffuse and cored/compact plaques in the anterior cingulate, frontal lobe (middle frontal gyrus), and parietal lobe, and showed additional correlations with diffuse plaque in the amygdala and occipital lobe, and with cored/compact plaque in the temporal lobe. Thus, commonly used PiB PET summary regions predominantly reflect diffuse plaque burden in ADAD and a mixture of diffuse and cored/compact plaque burden in LOAD. In direct comparisons of ADAD and LOAD, postmortem stereology identified much greater mean amyloid-β plaque burdens in ADAD versus LOAD across almost all brain regions studied. However, standard PiB PET did not recapitulate these stereologic findings, likely due to non-trivial amyloid-β plaque burdens in ADAD within the cerebellum and brainstem – commonly used reference regions in PiB PET. Our findings suggest that PiB PET summary regions correlate with amyloid-β plaque burden in both ADAD and LOAD; however, they might not be reliable in direct comparisons of regional amyloid-β plaque burden between the two forms of AD.
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    Longitudinal head-to-head comparison of 11C-PiB and 18F-florbetapir PET in a Phase 2/3 clinical trial of anti-amyloid-β monoclonal antibodies in dominantly inherited Alzheimer disease
    (Springer, 2023) Chen, Charles D.; McCullough, Austin; Gordon, Brian; Joseph-Mathurin, Nelly; Flores, Shaney; McKay, Nicole S.; Hobbs, Diana A.; Hornbeck, Russ; Fagan, Anne M.; Cruchaga, Carlos; Goate, Alison M.; Perrin, Richard J.; Wang, Guoqiao; Li, Yan; Shi, Xinyu; Xiong, Chengjie; Pontecorvo, Michael J.; Klein, Gregory; Su, Yi; Klunk, William E.; Jack, Clifford; Koeppe, Robert; Snider, B. Joy; Berman, Sarah B.; Roberson, Erik D.; Brosch, Jared; Surti, Ghulam; Jiménez-Velázquez, Ivonne Z.; Galasko, Douglas; Honig, Lawrence S.; Brooks, William S.; Clarnette, Roger; Wallon, David; Dubois, Bruno; Pariente, Jérémie; Pasquier, Florence; Sanchez-Valle, Raquel; Shcherbinin, Sergey; Higgins, Ixavier; Tunali, Ilke; Masters, Colin L.; van Dyck, Christopher H.; Masellis, Mario; Hsiung, Robin; Gauthier, Serge; Salloway, Steve; Clifford, David B.; Mills, Susan; Supnet-Bell, Charlene; McDade, Eric; Bateman, Randall J.; Benzinger, Tammie L. S.; DIAN-TU Study Team; Neurology, School of Medicine
    Purpose: Pittsburgh Compound-B (11C-PiB) and 18F-florbetapir are amyloid-β (Aβ) positron emission tomography (PET) radiotracers that have been used as endpoints in Alzheimer's disease (AD) clinical trials to evaluate the efficacy of anti-Aβ monoclonal antibodies. However, comparing drug effects between and within trials may become complicated if different Aβ radiotracers were used. To study the consequences of using different Aβ radiotracers to measure Aβ clearance, we performed a head-to-head comparison of 11C-PiB and 18F-florbetapir in a Phase 2/3 clinical trial of anti-Aβ monoclonal antibodies. Methods: Sixty-six mutation-positive participants enrolled in the gantenerumab and placebo arms of the first Dominantly Inherited Alzheimer Network Trials Unit clinical trial (DIAN-TU-001) underwent both 11C-PiB and 18F-florbetapir PET imaging at baseline and during at least one follow-up visit. For each PET scan, regional standardized uptake value ratios (SUVRs), regional Centiloids, a global cortical SUVR, and a global cortical Centiloid value were calculated. Longitudinal changes in SUVRs and Centiloids were estimated using linear mixed models. Differences in longitudinal change between PET radiotracers and between drug arms were estimated using paired and Welch two sample t-tests, respectively. Simulated clinical trials were conducted to evaluate the consequences of some research sites using 11C-PiB while other sites use 18F-florbetapir for Aβ PET imaging. Results: In the placebo arm, the absolute rate of longitudinal change measured by global cortical 11C-PiB SUVRs did not differ from that of global cortical 18F-florbetapir SUVRs. In the gantenerumab arm, global cortical 11C-PiB SUVRs decreased more rapidly than global cortical 18F-florbetapir SUVRs. Drug effects were statistically significant across both Aβ radiotracers. In contrast, the rates of longitudinal change measured in global cortical Centiloids did not differ between Aβ radiotracers in either the placebo or gantenerumab arms, and drug effects remained statistically significant. Regional analyses largely recapitulated these global cortical analyses. Across simulated clinical trials, type I error was higher in trials where both Aβ radiotracers were used versus trials where only one Aβ radiotracer was used. Power was lower in trials where 18F-florbetapir was primarily used versus trials where 11C-PiB was primarily used. Conclusion: Gantenerumab treatment induces longitudinal changes in Aβ PET, and the absolute rates of these longitudinal changes differ significantly between Aβ radiotracers. These differences were not seen in the placebo arm, suggesting that Aβ-clearing treatments may pose unique challenges when attempting to compare longitudinal results across different Aβ radiotracers. Our results suggest converting Aβ PET SUVR measurements to Centiloids (both globally and regionally) can harmonize these differences without losing sensitivity to drug effects. Nonetheless, until consensus is achieved on how to harmonize drug effects across radiotracers, and since using multiple radiotracers in the same trial may increase type I error, multisite studies should consider potential variability due to different radiotracers when interpreting Aβ PET biomarker data and, if feasible, use a single radiotracer for the best results.