@article{5c03751287a649188271dc9d7645f31b,
title = "TDP-43 pathology effect on volume and flortaucipir uptake in Alzheimer's disease",
abstract = "Introduction: Alzheimer's disease (AD) patients ≥70 years show smaller medial temporal volumes despite less 18F-flortaucipir-positron emission tomography (PET) uptake than younger counterparts. We investigated whether TAR DNA-binding protein 43 (TDP-43) was contributing to this volume-uptake mismatch. Methods: Seventy-seven participants with flortaucipir-PET and volumetric magnetic resonance imaging underwent postmortem AD and TDP-43 pathology assessments. Bivariate-response linear regression estimated the effect of age and TDP-43 pathology on volume and/or flortaucipir standardized uptake volume ratios of the hippocampus, amygdala, entorhinal, inferior temporal, and midfrontal cortices. Results: Older participants had lower hippocampal volumes and overall flortaucipir uptake. TDP-43-immunoreactivity correlated with reduced medial temporal volumes but was unrelated to flortaucipir uptake. TDP-43 effect size was consistent across the age spectrum. However, at older ages, the cohort mean volumes moved toward those of TDP-43-positives, reflecting the increasing TDP-43 pathology frequency with age. Discussion: TDP-43 pathology is a relevant contributor driving the volume-uptake mismatch in older AD participants. Highlights: TDP-43 pathology affects medial temporal volume loss but not tau radiotracer uptake. Greater TDP-43 pathology effect is seen in old age due to its increasing frequency. TDP-43 pathology is a relevant driver of the volume-uptake mismatch in old AD patients.",
keywords = "aging, Alzheimer's disease, dementia, tau-PET, TDP-43 pathology, volumetric MRI",
author = "Carlos, {Arenn F.} and Nirubol Tosakulwong and Weigand, {Stephen D.} and Senjem, {Matthew L.} and Christopher Schwarz and Knopman, {David S} and Boeve, {Bradley F.} and Petersen, {Ronald C.} and Nguyen, {Aivi T.} and Reichard, {R. Ross} and Dickson, {Dennis W} and Jack, {Clifford R Jr.} and Val Lowe and Whitwell, {Jennifer L.} and Josephs, {Keith A.}",
note = "Funding Information: The authors thank our patients and their families for their participation. The authors also thank AVID Radiopharmaceuticals, Inc., for their support in supplying the AV‐1451 precursor, chemistry production advice and oversight, and FDA regulatory cross‐filing permission and documentation needed for this work. However, they were not involved in funding, data analysis, interpretation or writing of the report. The work was supported by the National Institutes of Health (grant numbers R01‐AG037491 (PI: KAJ), RF1‐NS112153 (PI: KAJ & JLW), R01‐AG50603 (PI: JLW), P30‐AG062677 (PI: RCP); U01‐ AG 006786 (PI: RCP); The Elsie and Marvin Dekelboum Family Foundation; and the Oxley Foundation. The funding sources had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. Funding Information: The authors have no conflicts of interest pertinent to this manuscript. and . have no disclosures to report. . and . received research funding from the NIH and declare no competing financial interests. . reported holding stock in Gilead Sciences, Inc., Inovio Pharmaceuticals, Medtronic, Oncothyreon, Inc., and PAREXEL International. . serves on a Data Safety Monitoring Board for the DIAN study. He served on a Data Safety monitoring Board for a tau therapeutic for Biogen but received no personal compensation. He is an investigator in clinical trials sponsored by Biogen, Lilly Pharmaceuticals and the University of Southern California. He has served as a consultant for Roche, Samus Therapeutics, Magellan Health and Alzeca Biosciences but receives no personal compensation. He receives funding from the NIH. . received personal fees from Roche, Merck, Biogen, Genentech, Eisai and GE Healthcare outside the submitted work. 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. . serves as a consultant for Bayer Schering Pharma, Philips Molecular Imaging, Piramal Imaging and GE Healthcare outside the submitted work and receives research support from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals related to PET imaging and the NIH. Author disclosures are available in the supporting information A.F.C., N.T., S.D.W., A.T.N., R.R.R C.G.S., B.F.B., D.W.D., J.L.W K.A.J M.L.S D.S.K R.C.P CRJ V.L Publisher Copyright: {\textcopyright} 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.",
year = "2022",
doi = "10.1002/alz.12878",
language = "English (US)",
journal = "Alzheimer's and Dementia",
issn = "1552-5260",
publisher = "Elsevier Inc.",
}