Plasma phosphorylated-tau181 as a predictive biomarker for Alzheimer’s amyloid, tau and FDG PET status
Xue‐Ning Shen(Fudan University), Yuyuan Huang(Fudan University), Shi-Dong Chen(Fudan University), Yu Guo(Qingdao University), Lan Tan(Qingdao University), Qiang Dong(Fudan University), Jin‐Tai Yu(Fudan University), Alzheimer’s Disease Neuroimaging Initiative(University of California, San Francisco), Michael W. Weiner(University of Southern California), Paul Aisen(University of Southern California), Ronald Petersen(Mayo Clinic), Clifford R. Jack(Mayo Clinic), William J. Jagust(University of Pennsylvania), John Q. Trojanowki(University of Southern California), Arthur W. Toga(University of Southern California), Laurel Beckett(Boston University), Robert C. Green(Boston University), Andrew J. Saykin(Washington University in St. Louis), John C. Morris(Washington University in St. Louis), Richard J. Perrin(Washington University in St. Louis), Leslie M. Shaw(Alzheimer's Association), María C. Carrillo(Alzheimer's Association), William C. Potter(National Institute of Mental Health), Lisa L. Barnes(National Institutes of Health), Marie Bernard(National Institutes of Health), Hector M. González(University of California San Diego), Carole Ho(National Institutes of Health), John K. Hsiao(National Institutes of Health), Jonathan Jackson(National Institutes of Health), Eliezer Masliah(Biogen (United States)), Donna Masterman(Biogen (United States)), Ozioma C. Okonkwo(University of Wisconsin–Madison), Richard Perrin(National Institutes of Health), Laurie Ryan(National Institutes of Health), Nina Silverberg(National Institutes of Health), Adam Fleisher(Eli Lilly (United States)), Juliet Fockler(University of California, San Francisco), Cat Conti(Northern California Institute for Research and Education), Dallas P. Veitch(University of California, San Francisco), John Neuhaus(University of California, San Francisco), Chengshi Jin(University of California, San Francisco), Rachel L. Nosheny(University of California, San Francisco), Miriam T. Ashford(Northern California Institute for Research and Education), Derek Flenniken(Northern California Institute for Research and Education), Adrienne Kormos(University of Southern California), Gustavo Jiménez(University of Southern California), Michael Donohue(University of Southern California), Devon Gessert(University of Southern California), Jennifer Salazar(University of Southern California), Caileigh Zimmerman(University of Southern California), Yuliana Cabrera(University of Southern California), Sarah Walter(University of Southern California), Garrett Miller(University of Southern California), Godfrey Coker(University of Southern California), Taylor Clanton(University of Southern California), Lindsey Hergesheimer(University of Southern California), Stephanie Smith(University of Southern California), Olusegun Adegoke(University of Southern California), Payam Mahboubi(University of Southern California), Shelley Moore(University of Southern California), Jeremy Pizzola(University of Southern California), Elizabeth Shaffer(University of Southern California), Brittany Sloan(University of Southern California), Danielle Harvey(Mayo Clinic), Bret Borowski(Mayo Clinic), Chad Ward(Mayo Clinic), Christopher G. Schwarz(Mayo Clinic in Arizona), David Jones(Mayo Clinic), Jeff Gunter(Mayo Clinic), Kejal Kantarci(Mayo Clinic), Matthew L. Senjem(Mayo Clinic), Prashanthi Vemuri(Mayo Clinic in Arizona), Robert C. Reid(Mayo Clinic in Arizona), Nick C. Fox(University College London), Ian B. Malone(University of Southern California), Paul M. Thompson(University of Southern California), Sophia I. Thomopoulos(University of Southern California), Talia M. Nir(University of Southern California), Neda Jahanshad(University of Southern California), Charles DeCarli(University of California, Davis), Alexander Knaack(University of California, Davis), Evan Fletcher(University of California, San Francisco), Duygu Tosun(University of California, San Francisco), Stephanie Rossi Chen(Fudan University), Mark Choe(University of Southern California), Karen Crawford(University of Southern California), Paul A. Yushkevich(University of Pennsylvania), Sandhitsu R. Das(University of Michigan), Robert A. Koeppe(Alzheimer's Association), Eric M. Reiman(Alzheimer's Association), Kewei Chen(Alzheimer's Association), Chet Mathis(University of Pittsburgh), Susan Landau(Washington University in St. Louis), Richard Perrin(Washington University in St. Louis), Nigel J. Cairns(Washington University in St. Louis), Erin Householder(Washington University in St. Louis), Erin Franklin(Washington University in St. Louis), Haley Bernhardt(Washington University in St. Louis), Lisa Taylor‐Reinwald(Washington University in St. Louis), Leslie M. Shaw(University of Pennsylvania), John Q. Trojanowki(University of Pennsylvania), Magdalena Korecka(University of Pennsylvania), Michal Figurski(University of Southern California), Karen Crawford(University of Southern California), Scott Neu(University of Southern California), Andrew J. Saykin(Indiana University Bloomington), Kwangsik Nho(Indiana University Bloomington), Shannon L. Risacher(Indiana University School of Medicine), Liana G. Apostolova(University of California, Los Angeles), Li Shen(Indiana University Bloomington), Tatiana Foroud(Indiana University Bloomington), Kelly Nudelman(Indiana University Bloomington), Kelley Faber(Indiana University Bloomington), Kristi Wilmes(University of California San Diego), Leon J. Thal(University of California San Diego), Zaven S. Khachaturian(National Institutes of Health), John K. Hsiao(National Institutes of Health), Lisa C. Silbert(Oregon Health & Science University), Betty Lind(Oregon Health & Science University), Rachel Crissey(Oregon Health & Science University), Jeffrey Kaye(Oregon Health & Science University), Raina Carter(Oregon Health & Science University), Sara Dolen(Oregon Health & Science University), Joseph Quinn(University of Southern California), Lon S. Schneider(University of Southern California), Sonia Pawluczyk(University of Southern California), Mauricio Becerra(University of Southern California), Liberty Teodoro(University of Southern California), Karen Dagerman(University of Southern California), Bryan M. Spann(University of Southern California), James B. Brewer(University of California San Diego), Helen Vanderswag(Eli Lilly (United States)), Adam Fleisher(Eli Lilly (United States)), Jaimie Ziolkowski(University of Michigan), Judith L. Heidebrink(University of Michigan), Lisa Zbizek-Nulph(University of Michigan), Joanne Lord(Mayo Clinic), Colleen S. Albers(Mayo Clinic), David S. Knopman(Mayo Clinic), Kris Johnson(Brigham and Women's Hospital), Javier Villanueva‐Meyer(Baylor College of Medicine), Valory Pavlik(Baylor College of Medicine), Nathaniel Pacini(Baylor College of Medicine), Ashley Lamb(Baylor College of Medicine), Joseph S. Kass(Baylor College of Medicine), Rachelle S. Doody(Baylor College of Medicine), Victoria Shibley(Baylor College of Medicine), Munir Chowdhury(Baylor College of Medicine), Susan Rountree(Baylor College of Medicine), Mimi Dang(Baylor College of Medicine), Yaakov Stern(Columbia University Irving Medical Center), Lawrence S. Honig(Columbia University Irving Medical Center), Akiva Mintz(Cleveland Clinic), Beau M. Ances(Washington University in St. Louis), David Winkfield(Washington University in St. Louis), Maria Carroll(Washington University in St. Louis), Georgia Stobbs-Cucchi(Washington University in St. Louis), Angela Oliver(Washington University in St. Louis), Mary L. Creech(Washington University in St. Louis), Mark A. Mintun(Washington University in St. Louis), Stacy Schneider(Washington University in St. Louis), David Geldmacher(University of Alabama at Birmingham), Marissa Natelson Love(University of Alabama at Birmingham), Randall Griffith(University of Alabama at Birmingham), David Clark(University of Alabama at Birmingham), John Brockington(University of Alabama at Birmingham), Daniel Marson(University of Alabama at Birmingham), Hillel Grossman(Icahn School of Medicine at Mount Sinai), Martin Goldstein(Icahn School of Medicine at Mount Sinai), Jonathan Greenberg(Icahn School of Medicine at Mount Sinai), Effie Mitsis(Rush University Medical Center), Raj C. Shah(Rush University Medical Center), Melissa Lamar(Rush University Medical Center), Patricia Samuels(Rush University Medical Center), Ranjan Duara, Maria T. Greig‐Custo, Rosemarie Rodriguez(Johns Hopkins University), Marilyn Albert(Johns Hopkins University), Chiadi Onyike(Johns Hopkins University), Leonie Farrington(Johns Hopkins University), Scott Rudow(Johns Hopkins University), Rottislav Brichko(Johns Hopkins University), Stephanie Kielb(Johns Hopkins University), Amanda Smith(University of South Florida), Balebail Ashok Raj(University of South Florida), Kristin Fargher(University of South Florida), Martin Sadowski(New York University), Thomas Wısnıewskı(New York University), Melanie Shulman(New York University), Arline Faustin(New York University), Julia Rao(New York University), Karen M. Castro(New York University), Anaztasia Ulysse(New York University), Shannon Chen(Fudan University), Mohammed O. Sheikh(New York University), Jamika Singleton-Garvin(Duke Medical Center), P. Murali Doraiswamy(Duke Medical Center), Jeffrey R. Petrella(Duke Medical Center), Olga James(Duke Medical Center), Terence Z. Wong(Duke Medical Center), Salvador Borges‐Neto(Duke Medical Center), Jason H. Karlawish(University of Pennsylvania), David A. Wolk(University of Pennsylvania), Sanjeev Vaishnavi(University of Pennsylvania), Christopher M. Clark(University of Pennsylvania), Steven E. Arnold(University of Kentucky), Charles D. Smith(University of Kentucky), Gregory A. Jicha(University of Kentucky), Riham El Khouli(University of Kentucky), Flavius D. Raslau(University of Kentucky), Oscar L. López(University of Pittsburgh), MaryAnn Oakley(University of Pittsburgh), Donna M. Simpson(University of Pittsburgh), Anton P. Porsteinsson(University of Rochester Medical Center), Kim Martin(University of Rochester Medical Center), Nancy Kowalski(University of Rochester Medical Center), Melanie Keltz(University of Rochester Medical Center), Bonnie S. Goldstein(University of Rochester Medical Center), Kelly M. Makino(University of Rochester Medical Center), M. Saleem Ismail(University of Rochester Medical Center), Connie Brand(University of California, Irvine), Gaby Thai(University of California, Irvine), Aimee Pierce(University of California, Irvine), Beatriz Yanez(University of California, Irvine), Elizabeth Sosa(University of California, Irvine), Megan Witbracht(University of California, Irvine), Brendan Kelley(The Ohio State University), Trung Nguyen(The University of Texas Southwestern Medical Center), Kyle Womack(The University of Texas Southwestern Medical Center), Dana Mathews(The University of Texas Southwestern Medical Center), Mary Quiceno(Emory University), Allan I. Levey(Emory University), James J. Lah(Emory University), Ihab Hajjar(Emory University), Janet S. Cellar(Emory University), Jeffrey M. Burns(University of Kansas Medical Center), Russell H. Swerdlow(University of Kansas Medical Center), William M. Brooks(University of California, Los Angeles), Daniel Silverman(University of California, Los Angeles), Sarah Kremen(University of California, Los Angeles), Liana G. Apostolova(University of California, Los Angeles), Kathleen Tingus(University of California, Los Angeles), Po H. Lu(University of California, Los Angeles), George Bartzokis(University of California, Los Angeles), Ellen Woo(University of California, Los Angeles), Edmond Teng(University of California, Los Angeles), Neill R. Graff‐Radford(Jacksonville College), Francine Parfitt(Jacksonville College), Kim Poki-Walker(Jacksonville College), Martin R. Farlow(Indiana University Bloomington), Ann Marie Hake(Indiana University Bloomington), Brandy R. Matthews(Indiana University Bloomington), Jared R. Brosch(Indiana University Bloomington), Scott Herring(Yale University), Christopher H. van Dyck(Yale University), Adam P. Mecca(Yale University), Susan P. Good(Yale University), Martha G. MacAvoy(Yale University), Richard E. Carson(Yale University), Pradeep Varma(Jewish General Hospital), Howard Chertkow(Jewish General Hospital), Susan Vaitekunis(Jewish General Hospital), Chris Hosein(Sunnybrook Health Science Centre), Sandra Black(Sunnybrook Health Science Centre), Bojana Stefanovic(Sunnybrook Health Science Centre), Chris Heyn, Ging‐Yuek Robin Hsiung, Ellen Kim, Benita Mudge, Vesna Sossi, Howard Feldman, Michele Assaly, Elizabeth Finger, Stephen Pasternak, Irina Rachinsky, Andrew Kertesz, Dick Drost, John Rogers(Northwestern University), Ian Grant(Northwestern University), Brittanie Muse(Northwestern University), Emily Rogalskı(Northwestern University), Jordan Robson(Northwestern University), M.‐Marsel Mesulam(Northwestern University), Diana Kerwin(Northwestern University), Chuang-Kuo Wu(Northwestern University), Nancy Johnson(Northwestern University), Kristine Lipowski(Northwestern University), Sandra Weıntraub(Northwestern University), Borna Bonakdarpour(Northwestern University), Nunzio Pomara(Nathan Kline Institute for Psychiatric Research), Raymundo Hernando(Nathan Kline Institute for Psychiatric Research), Antero Sarrael(Nathan Kline Institute for Psychiatric Research), Howard J. Rosen(University of California, San Francisco), Bruce L. Miller(University of California, San Francisco), David C. Perry(University of California, San Francisco), Raymond Scott Turner(Georgetown University), Kathleen Johnson(Brigham and Women's Hospital), Brigid Reynolds(Georgetown University), Kelly McCann(Georgetown University), Jessica Poe(Brigham and Women's Hospital), Reisa A. Sperling(Brigham and Women's Hospital), Keith A. Johnson(Brigham and Women's Hospital), Gad A. Marshall(Brigham and Women's Hospital), Christine M. Belden(Banner Sun Health Research Institute), Alireza Atri(Banner Sun Health Research Institute), Bryan M. Spann(University of Southern California), Kelly A. Clark(Banner Sun Health Research Institute), Edward Zamrini(Banner Sun Health Research Institute), Marwan N. Sabbagh(Cleveland Clinic), Ronald Killiany, Robert A. Stern, Jesse Mez, Neil W. Kowall, Andrew E. Budson(Howard University), Thomas O. Obisesan(Howard University), Oyonumo Ntekim(Howard University), Saba Wolday(Howard University), Javed Khan(Howard University), Evaristus Nwulia(Howard University), Sheeba Nadarajah(Howard University), Alan J. Lerner(Case Western Reserve University), Paula Ogrocki(Case Western Reserve University), Curtis Tatsuoka(Case Western Reserve University), Parianne Fatica(Case Western Reserve University), Evan Fletcher(University of California, Davis), Pauline Maillard(University of California, Davis), John Olichney(University of California, Davis), Charles DeCarli(University of California, Davis), Owen Carmichael(Dent Neurologic Institute), Vernice Bates(Dent Neurologic Institute), Horacio Capote(Dent Neurologic Institute), Michelle Rainka(Dent Neurologic Institute), Michael Borrie(Parkwood Institute), T‐Y Lee(Parkwood Institute), Robert Bartha(University of Wisconsin–Madison), Sterling C. Johnson(University of Wisconsin–Madison), Sanjay Asthana(University of Wisconsin–Madison), Cynthia M. Carlsson(Alzheimer's Association), Allison Perrin(Alzheimer's Association), Anna Burke(Alzheimer's Association), Douglas W. Scharre(The Ohio State University), Maria Kataki(The Ohio State University), Rawan Tarawneh(The Ohio State University), Brendan Kelley(The Ohio State University), David Hart(Albany Medical Center Hospital), Earl A. Zimmerman(Albany Medical Center Hospital), Dzintra Celmins(University of Iowa), Del D. Miller(University of Iowa), Laura L. Boles Ponto(University of Iowa), Karen Ekstam Smith(University of Iowa), Hristina Koleva(University of Iowa), Hyungsub Shim(University of Iowa), Ki Won Nam(University of Iowa), Susan K. Schultz(Wake Forest University), Jeff D. Williamson(Wake Forest University), Suzanne Craft(Wake Forest University), Jo Cleveland(Wake Forest University), Mia Yang(Wake Forest University), Kaycee M. Sink(Providence College), Brian R. Ott(Providence College), Jonathan Drake(Providence College), Geoffrey Tremont(Providence College), Lori A. Daiello(Providence College), Jonathan Drake(Providence College), Marwan N. Sabbagh(Cleveland Clinic), Aaron Ritter(Cleveland Clinic), Charles Bernick(Cleveland Clinic), Donna Munic(Cleveland Clinic), Akiva Mintz(Cleveland Clinic), Abigail O’Connelll(Roper St. Francis Healthcare), Jacobo Mintzer(Roper St. Francis Healthcare), Arthur Wiliams(Houston Methodist), Joseph C. Masdeu(Houston Methodist), Jiong Shi(Barrow Neurological Institute), Angelica Garcia(Barrow Neurological Institute), Marwan N. Sabbagh(Cleveland Clinic), Paul Newhouse(Vanderbilt University Medical Center), Steven G. Potkin(Providence College), Stephen Salloway(Providence College), Paul Malloy(Providence College), Stephen Correia(Providence College), Smita Kittur(Hartford Hospital), Godfrey D. Pearlson(Hartford Hospital), Karen Blank(Hartford Hospital), Karen Anderson(Dartmouth–Hitchcock Medical Center), Laura A. Flashman(Dartmouth–Hitchcock Medical Center), Marc Seltzer(Dartmouth–Hitchcock Medical Center), Mary L. Hynes(Dartmouth–Hitchcock Medical Center), Robert B. Santulli(Dartmouth–Hitchcock Medical Center), Norman Relkin(Cornell University), Gloria Chiang(Cornell University), Michael Lin(Cornell University), Lisa Ravdin(Cornell University), Athena Lee(Cornell University), Ron Petersen(Mayo Clinic), Thomas C. Neylan(Northwestern University), Jordan Grafman(Northwestern University), Tom Montine(University of Southern California), Sarah Danowski(University of Southern California), Catherine Nguyen-Barrera(University of Southern California), Shannon Finley(Fudan University), Danielle Harvey(Rush University), Michael Donohue(University of Southern California), Matt A. Bernstein(University of California, San Francisco), Norm Foster(University of Utah), Tatiana Foroud(Indiana University Bloomington), Steven G. Potkin(UC Irvine Health), Li Shen(Indiana University Bloomington), Kelley Faber(Indiana University Bloomington), Sung Eun Kim(Indiana University Bloomington), Kwangsik Nho(Indiana University Bloomington), Kristi Wilmes(University of California San Diego), Helen Vanderswag(University of California San Diego), Adam Fleisher(Rush University Medical Center), Ajay Sood(Rush University Medical Center), Kimberly S. Blanchard(Rush University Medical Center), Debra Fleischman(Rush University Medical Center), Maria T. Greig(University of Rochester Medical Center), Bonnie S. Goldstein(University of Rochester Medical Center), Kimberly S. Martin(University of California, Irvine), Gaby Thai(University of California, Irvine), Aimee Pierce(University of California, Irvine), Christopher Reist(University of California, Irvine), Beatriz Yanez(University of California, Irvine), Elizabeth Sosa(University of California, Irvine), Megan Witbracht(University of California, Irvine), Carl Sadowsky(Palm Beach Neurology), Walter Martínez(Palm Beach Neurology), Teresa Villena(University of California, San Francisco), Howard J. Rosen(University of California, San Francisco), Elaine R. Peskind(University of Washington), Eric C. Petrie(University of Washington), Gail Li(University of Washington), Jerome A. Yesavage(Stanford University), Joy L. Taylor(Stanford University), Steven Chao(Stanford University), Jaila Coleman(Stanford University), Jessica D. White(Stanford University), Barton Lane(Stanford University), Allyson Rosen(Stanford University), Jared Tinklenberg(University of Southern California), Gustavo Jimenez‐Maggiora(Boston University), Erin Drake(Boston University), Mike Donohue(University of Southern California), Craig Nelson(University of California, San Francisco), David Bickford(University of Pittsburgh), Meryl A. Butters(University of Pittsburgh), Michelle Zmuda(University of Pittsburgh), Bret Borowski(Mayo Clinic), Jeff Gunter(Mayo Clinic), Matthew L. Senjem(Mayo Clinic), Kejal Kantarci(Mayo Clinic), Chad Ward(Mayo Clinic), Denise A. Reyes(Mayo Clinic), Kelley Faber(Indiana University Bloomington), Kelly Nudelman(University of California, San Francisco), Yiu Ho Au(University of California, San Francisco), Kelly Scherer(University of California, San Francisco), Daniel Catalinotto(University of California, San Francisco), Samuel Stark(University of California, San Francisco), Elise Ong(University of California, San Francisco), Dariella Fernandez(University of Pittsburgh), Michelle Zmuda(University of Pittsburgh)
Cited by 70Open Access
Abstract
Plasma phosphorylated-tau181 (p-tau181) showed the potential for Alzheimer's diagnosis and prognosis, but its role in detecting cerebral pathologies is unclear. We aimed to evaluate whether it could serve as a marker for Alzheimer's pathology in the brain. A total of 1189 participants with plasma p-tau181 and PET data of amyloid, tau or FDG PET were included from ADNI. Cross-sectional relationships of plasma p-tau181 with PET biomarkers were tested. Longitudinally, we further investigated whether different p-tau181 levels at baseline predicted different progression of Alzheimer's pathological changes in the brain. We found plasma p-tau181 significantly correlated with brain amyloid (Spearman ρ = 0.45, P < 0.0001), tau (0.25, P = 0.0003), and FDG PET uptakes (-0.37, P < 0.0001), and increased along the Alzheimer's continuum. Individually, plasma p-tau181 could detect abnormal amyloid, tau pathologies and hypometabolism in the brain, similar with or even better than clinical indicators. The diagnostic accuracy of plasma p-tau181 elevated significantly when combined with clinical information (AUC = 0.814 for amyloid PET, 0.773 for tau PET, and 0.708 for FDG PET). Relationships of plasma p-tau181 with brain pathologies were partly or entirely mediated by the corresponding CSF biomarkers. Besides, individuals with abnormal plasma p-tau181 level (>18.85 pg/ml) at baseline had a higher risk of pathological progression in brain amyloid (HR: 2.32, 95%CI 1.32-4.08) and FDG PET (3.21, 95%CI 2.06-5.01) status. Plasma p-tau181 may be a sensitive screening test for detecting brain pathologies, and serve as a predictive biomarker for Alzheimer's pathophysiology.
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