TY - JOUR
T1 - Comparing PET and MRI Biomarkers Predicting Cognitive Decline in Preclinical Alzheimer Disease
AU - Mayblyum, D.V.
AU - Becker, J.A.
AU - Jacobs, H.I.L.
AU - Buckley, R.F.
AU - Schultz, A.P.
AU - Sepulcre, J.
AU - Sanchez, J.S.
AU - Rubinstein, Z.B.
AU - Katz, S.R.
AU - Moody, K.A.
AU - Vannini, P.
AU - Papp, K.V.
AU - Rentz, D.M.
AU - Price, J.C.
AU - Sperling, R.A.
AU - Johnson, K.A.
AU - Hanseeuw, B.J.
N1 - Funding Information:
D.V. Mayblyum, J.A. Becker, H.I.L. Jacobs, R.F. Buckley, A.P. Schultz, J. Sepulcre, J.S. Sanchez, Z.B. Rubinstein, S.R. Katz, K.A. Moody, P. Vannini, and K.V. Papp report no disclosures relevant to the manuscript. D.M. Rentz reports support from Eli Lilly, Neurotrack, and Biogen outside the submitted work. J.C. Price reports no disclosures relevant to the manuscript. R.A. Sperling reports funding from Janssen and personal fees from AC Immune, Biogen, and Roche outside the submitted work. K.A. Johnson reports personal fees from Biogen, Lilly/Avid, Merck, Novartis, Takeda, Roche/Genentech, and Janssen, as well as grants from the Alzheimer's Association, Alzheimer's Drug Discovery Foundation, and NIH. B.J. Hanseeuw reports grants from the Belgian National Fund for Scientific Research and the Belgian Foundation for Alzheimer Research during the conduct of the study. Go to Neurology.org/N for full disclosures.
Funding Information:
Study funded by NIH grants P01AG036694 (R.A. Sperling and K.A. Johnson), R01 AG046396 (K.A. Johnson), R01AG061811 (J. Sepulcre), and R01AG061445 (J. Sepulcre); the Belgian Fund for Scientific Research (FNRS No. SPD 28094292; B.J. Hanseeuw); and the Belgian Foundation for Alzheimer Research (SAO-FRA No. P16.008, B.J. Hanseeuw). H.I.L. Jacobs received funding from the European Union's Horizon 2020 Research and Innovation Programme under the Marie Sklodowska-Curie Grant agreement (IF-2015-GF, 706714) and NIH–National Institute on Aging grant R01AG062559. P. Vannini is supported by K01 awards by the National Institute on Aging. K.V. Papp received NIH support through grant 5K23AG053422-03.
Publisher Copyright:
Copyright © 2021 American Academy of Neurology
PY - 2021/6/15
Y1 - 2021/6/15
N2 - Objective To compare how structural MRI, fluorodeoxyglucose (FDG), and flortaucipir (FTP) PET signals predict cognitive decline in high-amyloid vs low-amyloid participants with the goal of determining which biomarker combination would result in the highest increase of statistical power for prevention trials. Methods In this prospective cohort study, we analyzed data from clinically normal adults from the Harvard Aging Brain Study with MRI, FDG, FTP, and Pittsburgh compound B (PiB)-PET acquired within a year and prospective cognitive evaluations over a mean 3-year follow-up. We focused analyses on predefined regions of interest: inferior temporal, isthmus cingulate, hippocampus, and entorhinal cortex. Cognition was assessed with the Preclinical Alzheimer's Cognitive Composite. We evaluated the association between biomarkers and cognitive decline using linear mixed-effect models with random intercepts and slopes, adjusting for demographics. We generated power curves simulating prevention trials. Results Data from 131 participants (52 women, age 73.98 +/- 8.29 years) were analyzed in the study. In separate models, most biomarkers had a closer association with cognitive decline in the high-PiB compared to the low-PiB participants. A backward stepwise regression including all biomarkers demonstrated that only neocortical PiB, entorhinal FTP, and entorhinal FDG were independent predictors of subsequent cognitive decline. Power analyses revealed that using both high PiB and low entorhinal FDG as inclusion criteria reduced 3-fold the number of participants needed in a hypothetical trial compared to using only high PiB. Discussion In preclinical Alzheimer disease, entorhinal hypometabolism is a strong and independent predictor of subsequent cognitive decline, making FDG a potentially useful biomarker to increase power in clinical trials. Classification of Evidence This study provides Class II evidence that in people with preclinical Alzheimer disease, entorhinal hypometabolism identified by FDG-PET is predictive of subsequent cognitive decline.
AB - Objective To compare how structural MRI, fluorodeoxyglucose (FDG), and flortaucipir (FTP) PET signals predict cognitive decline in high-amyloid vs low-amyloid participants with the goal of determining which biomarker combination would result in the highest increase of statistical power for prevention trials. Methods In this prospective cohort study, we analyzed data from clinically normal adults from the Harvard Aging Brain Study with MRI, FDG, FTP, and Pittsburgh compound B (PiB)-PET acquired within a year and prospective cognitive evaluations over a mean 3-year follow-up. We focused analyses on predefined regions of interest: inferior temporal, isthmus cingulate, hippocampus, and entorhinal cortex. Cognition was assessed with the Preclinical Alzheimer's Cognitive Composite. We evaluated the association between biomarkers and cognitive decline using linear mixed-effect models with random intercepts and slopes, adjusting for demographics. We generated power curves simulating prevention trials. Results Data from 131 participants (52 women, age 73.98 +/- 8.29 years) were analyzed in the study. In separate models, most biomarkers had a closer association with cognitive decline in the high-PiB compared to the low-PiB participants. A backward stepwise regression including all biomarkers demonstrated that only neocortical PiB, entorhinal FTP, and entorhinal FDG were independent predictors of subsequent cognitive decline. Power analyses revealed that using both high PiB and low entorhinal FDG as inclusion criteria reduced 3-fold the number of participants needed in a hypothetical trial compared to using only high PiB. Discussion In preclinical Alzheimer disease, entorhinal hypometabolism is a strong and independent predictor of subsequent cognitive decline, making FDG a potentially useful biomarker to increase power in clinical trials. Classification of Evidence This study provides Class II evidence that in people with preclinical Alzheimer disease, entorhinal hypometabolism identified by FDG-PET is predictive of subsequent cognitive decline.
KW - ASSOCIATION
KW - BETA
KW - METABOLISM
KW - TAU PET
U2 - 10.1212/WNL.0000000000012108
DO - 10.1212/WNL.0000000000012108
M3 - Article
C2 - 33952655
SN - 0028-3878
VL - 96
SP - E2933-E2943
JO - Neurology
JF - Neurology
IS - 24
ER -