Selecting software pipelines for change in flortaucipir SUVR: Balancing repeatability and group separation.

Since tau PET tracers were introduced, investigators have quantified them using a wide variety of automated methods. As longitudinal cohort studies acquire second and third time points of serial within-person tau PET data, determining the best pipeline to measure change has become crucial. We compared a total of 415 different quantification methods (each a combination of multiple options) according to their effects on a) differences in annual SUVR change between clinical groups, and b) longitudinal measurement repeatability as measured by the error term from a linear mixed-effects model. Our comparisons used MRI and Flortaucipir scans of 97 Mayo Clinic study participants who clinically either: a) were cognitively unimpaired, or b) had cognitive impairments that were consistent with Alzheimer's disease pathology. Tested methods included cross-sectional and longitudinal variants of two overarching pipelines (FreeSurfer 6.0, and an in-house pipeline based on SPM12), three choices of target region (entorhinal, inferior temporal, and a temporal lobe meta-ROI), five types of partial volume correction (PVC) (none, two-compartment, three-compartment, geometric transfer matrix (GTM), and a tau-specific GTM variant), seven choices of reference region (cerebellar crus, cerebellar gray matter, whole cerebellum, pons, supratentorial white matter, eroded supratentorial WM, and a composite of eroded supratentorial WM, pons, and whole cerebellum), two choices of region masking (GM or GM and WM), and two choices of statistic (voxel-wise mean vs. median). Our strongest findings were: 1) larger temporal-lobe target regions greatly outperformed entorhinal cortex (median sample size estimates based on a hypothetical clinical trial were 520-526 vs. 1740); 2) longitudinal processing pipelines outperformed cross-sectional pipelines (median sample size estimates were 483 vs. 572); and 3) reference regions including supratentorial WM outperformed traditional cerebellar and pontine options (median sample size estimates were 370 vs. 559). Altogether, our results favored longitudinally SUVR methods and a temporal-lobe meta-ROI that includes adjacent (juxtacortical) WM, a composite reference region (eroded supratentorial WM + pons + whole cerebellum), 2-class voxel-based PVC, and median statistics.

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Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

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Declaration of Competing Interest Christopher Schwarz receives research support from the NIH. Terry Therneau reports no disclosures. Stephen Weigand reports no disclosures. Jeffrey Gunter reports no disclosures. Val Lowe consults for Bayer Schering Pharma, Piramal Life Sciences, Eisai, Inc., and Merck Research and receives research support from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals and the NIH (NIA, NCI). Scott Przybelski reports no disclosures. Prashanthi Vemuri is funded by the NIH. Matthew Senjem has owned stock in medical related companies, unrelated to the current work within the past 12 months: Align Technology, Inc., Inovio Pharmaceuticals, Inc., LHC Group, Inc., Mesa Laboratories, Inc., Natus Medical Inc., and Varex Imaging Corporation. He has also owned stock in these medical related companies within the past three years, unrelated to the current work: CRISPR Therapeutics, Gilead Sciences, Inc., Ionis Pharmaceuticals, Johnson & Johnson, Medtronic, Inc. Hugo Botha is funded by the NIH. Kejal Kantarci serves on the data safety monitoring board for Takeda Global Research and Development Center, Inc., receives research support from Avid Radioparmaceuticals and Eli Lilly, and receives funding from NIH and Alzheimer's Drug Discovery Foundation. Bradley Boeve has served as an investigator for clinical trials sponsored by Axovant and Biogen. He receives royalties from the publication of a book entitled Behavioral Neurology Of Dementia (Cambridge Medicine, 2009, 2017). He serves on the Scientific Advisory Board of the Tau Consortium. He receives research support from the NIH, the Mayo Clinic Dorothy and Harry T. Mangurian Jr. Lewy Body Dementia Program and the Little Family Foundation. Jennifer Whitwell is funded by the NIH. Keith Josephs is funded by the NIH. Ronald Petersen is a consultant for Roche, Inc., Biogen, Inc., and Eisai, Inc., served on a DSMB for Genentech, Inc.; receives royalties from publishing Mild Cognitive Impairment (Oxford University Press, 2003) and UpToDate; and receives research support from the NIH (P30 AG062677 (PI) and U01-AG006786 (PI), R01-AG011378 (Co-I), and U01–024904 (Co-I)). David Knopman serves on a Data Safety Monitoring Board for the DIAN study; is an investigator in clinical trials sponsored by Biogen and Lilly Pharmaceuticals; and receives research support from the NIH. Clifford Jack serves on an independent data monitoring board for Roche, has served as a speaker for Eisai, and consulted for Biogen, but he receives no personal compensation from any commercial entity. He receives research support from NIH and the Alexander Family Alzheimer's Disease Research Professorship of the Mayo Clinic.