EBioMedicine (May 2024)

Deconstructing pathological tau by biological process in early stages of Alzheimer disease: a method for quantifying tau spatial spread in neuroimagingResearch in context

  • Stephanie Doering,
  • Austin McCullough,
  • Brian A. Gordon,
  • Charles D. Chen,
  • Nicole McKay,
  • Diana Hobbs,
  • Sarah Keefe,
  • Shaney Flores,
  • Jalen Scott,
  • Hunter Smith,
  • Stephen Jarman,
  • Kelley Jackson,
  • Russ C. Hornbeck,
  • Beau M. Ances,
  • Chengjie Xiong,
  • Andrew J. Aschenbrenner,
  • Jason Hassenstab,
  • Carlos Cruchaga,
  • Alisha Daniels,
  • Randall J. Bateman,
  • John C. Morris,
  • Tammie L.S. Benzinger,
  • James M. Noble,
  • Gregory S. Day,
  • Neill R. Graff-Radford,
  • Jonathan Voglein,
  • Johannes Levin,
  • Ricardo F. Allegri,
  • Patricio Chrem Mendez,
  • Ezequiel Surace,
  • Sarah B. Berman,
  • Snezana Ikonomovic,
  • Neelesh K. Nadkarni,
  • Francisco Lopera,
  • Laura Ramirez,
  • David Aguillon,
  • Yudy Leon,
  • Claudia Ramos,
  • Diana Alzate,
  • Ana Baena,
  • Natalia Londono,
  • Sonia Moreno,
  • Mathias Jucker,
  • Christoph Laske,
  • Elke Kuder-Buletta,
  • Susanne Graber-Sultan,
  • Oliver Preische,
  • Anna Hofmann,
  • Takeshi Ikeuchi,
  • Kensaku Kasuga,
  • Yoshiki Niimi,
  • Kenji Ishii,
  • Michio Senda,
  • Raquel Sanchez-Valle,
  • Pedro Rosa-Neto,
  • Nick C. Fox,
  • Dave Cash,
  • Jae-Hong Lee,
  • Jee Hoon Roh,
  • Stephen Salloway,
  • Meghan C. Riddle,
  • William Menard,
  • Courtney Bodge,
  • Mustafa Surti,
  • Leonel Tadao Takada,
  • Martin Farlow,
  • Jasmeer P. Chhatwal,
  • V.J. Sanchez-Gonzalez,
  • Maribel Orozco-Barajas,
  • Alison M. Goate,
  • Alan E. Renton,
  • Bianca T. Esposito,
  • Celeste M. Karch,
  • Jacob Marsh,
  • Carlos Cruchaga,
  • Victoria Fernanadez,
  • Brian A. Gordon,
  • Anne M. Fagan,
  • Gina Jerome,
  • Elizabeth Herries,
  • Jorge Llibre-Guerra,
  • Allan I. Levey,
  • Erik C.B. Johnson,
  • Nicholas T. Seyfried,
  • Peter R. Schofield,
  • William S. Brooks,
  • Jacob A. Bechara,
  • Randall Bateman,
  • Eric McDade,
  • Jason Hassenstab,
  • Richard J. Perrin,
  • Erin E. Franklin,
  • Tammie Benzinger,
  • Allison Chen,
  • Charles Chen,
  • Shaney Flores,
  • Nelly Friedrichsen,
  • Brian Gordon,
  • Nancy Hantler,
  • Russ Hornbeck,
  • Steve Jarman,
  • Sarah Keefe,
  • Deborah Koudelis,
  • Parinaz Massoumzadeh,
  • Austin McCullough,
  • Nicole McKay,
  • Joyce Nicklaus,
  • Christine Pulizos,
  • Qing Wang,
  • Sheetal Mishall,
  • Edita Sabaredzovic,
  • Emily Deng,
  • Madison Candela,
  • Hunter Smith,
  • Diana Hobbs,
  • Jalen Scott,
  • Johannes Levin,
  • Chengjie Xiong,
  • Peter Wang,
  • Xiong Xu,
  • Yan Li,
  • Emily Gremminger,
  • Yinjiao Ma,
  • Ryan Bui,
  • Ruijin Lu,
  • Ralph Martins,
  • Ana Luisa Sosa Ortiz,
  • Alisha Daniels,
  • Laura Courtney,
  • Hiroshi Mori,
  • Charlene Supnet-Bell,
  • Jinbin Xu,
  • John Ringman,
  • Nicolas Barthelemy,
  • John Morris,
  • Jennifer Smith

Journal volume & issue
Vol. 103
p. 105080

Abstract

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Summary: Background: Neuroimaging studies often quantify tau burden in standardized brain regions to assess Alzheimer disease (AD) progression. However, this method ignores another key biological process in which tau spreads to additional brain regions. We have developed a metric for calculating the extent tau pathology has spread throughout the brain and evaluate the relationship between this metric and tau burden across early stages of AD. Methods: 445 cross-sectional participants (aged ≥ 50) who had MRI, amyloid PET, tau PET, and clinical testing were separated into disease-stage groups based on amyloid positivity and cognitive status (older cognitively normal control, preclinical AD, and symptomatic AD). Tau burden and tau spatial spread were calculated for all participants. Findings: We found both tau metrics significantly elevated across increasing disease stages (p < 0.0001) and as a function of increasing amyloid burden for participants with preclinical (p < 0.0001, p = 0.0056) and symptomatic (p = 0.010, p = 0.0021) AD. An interaction was found between tau burden and tau spatial spread when predicting amyloid burden (p = 0.00013). Analyses of slope between tau metrics demonstrated more spread than burden in preclinical AD (β = 0.59), but then tau burden elevated relative to spread (β = 0.42) once participants had symptomatic AD, when the tau metrics became highly correlated (R = 0.83). Interpretation: Tau burden and tau spatial spread are both strong biomarkers for early AD but provide unique information, particularly at the preclinical stage. Tau spatial spread may demonstrate earlier changes than tau burden which could have broad impact in clinical trial design. Funding: This research was supported by the Knight Alzheimer Disease Research Center (Knight ADRC, NIH grants P30AG066444, P01AG026276, P01AG003991), Dominantly Inherited Alzheimer Network (DIAN, NIH grants U01AG042791, U19AG03243808, R01AG052550-01A1, R01AG05255003), and the Barnes-Jewish Hospital Foundation Willman Scholar Fund.

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