Associations between near end-of-life flortaucipir PET and postmortem CTE-related tau neuropathology in six former American football players
Authors: Alosco Michael L. , Su Yi , Stein Thor D. , Protas Hillary , Cherry Jonathan D. , Adler Charles H. , Balcer Laura J. , Bernick Charles , Pulukuri Surya Vamsi , Abdolmohammadi Bobak , Coleman Michael J. , Palmisano Joseph N. , Tripodis Yorghos , Mez Jesse , Rabinovici Gil D. , Marek Kenneth L. , Beach Thomas G. , Johnson Keith A. , Huber Bertrand Russell , Koerte Inga , Lin Alexander P. , Bouix Sylvain , Cummings Jeffrey L. , Shenton Martha E. , Reiman Eric M. , McKee Ann C. , Stern Robert A. ,   for the DIAGNOSE C. T. E. Research Project, Reiman Eric , Su Yi , Chen Kewei , Protas Hillary , Boker Connie , Alosco Michael L. , Au Rhoda , Cantu Robert C. , Farrer Lindsay , Helm Robert , Katz Douglas I. , Kowall Neil , Mez Jesse , Mercier Gustavo , Otis James , Stern Robert A. , Weller Jason , Simkin Irene , Andino Alondra , Conneely Shannon , Diamond Courtney , Fagle Tessa , Haller Olivia , Hunt Tennyson , Gullotti Nicole , Mariani Megan , Mayville Brian , McLaughlin Kathleen , Nanna Mary , Platt Taylor , Pulukuri Surya , Rice Fiona , Sestak Madison , McClean Michael , Tripodis Yorghos , Annis Douglas , Chaisson Christine , Dixon Diane B. , Finney Carolyn , Gallagher Kerrin , Hartlage Kaitlin , Lu Jun , Martin Brett , Ojo Emmanuel , Palmisano Joseph N. , Pine Brittany , Ramachandran Janani , Bouix Sylvain , Fitzsimmons Jennifer , Lin Alexander P. , Koerte Inga K. , Pasternak Ofer , Shenton Martha E. , Arcinieago Hector , Billah Tashrif , Bonke Elena , Breedlove Katherine , Coello Eduardo , Coleman Michael J. , Jung Leonhard , Liao Huijun , Loy Maria , Rizzoni Elizabeth , Schultz Vivian , Silva Annelise , Vessey Brynn , Wiegand Tim L. T. , Banks Sarah , Bernick Charles , Miller Jason , Ritter Aaron , Sabbagh Marwan , de la Cruz Raelynn , Durant Jan , Golceker Morgan , Harmon Nicolette , Kaylegian Kaeson , Long Rachelle , Nance Christin , Sandoval Priscilla , Turner Robert W. , Marek Kenneth L. , Serrano Andrew , Adler Charles H. , Dodick David W. , Geda Yonas , Wethe Jennifer V. , Falk Bryce , Duffy Amy , Howard Marci , Montague Michelle , Osgood Thomas , Babcock Debra , Bellgowan Patrick , Balcer Laura , Barr William , Goldberg Judith , Wisniewski Thomas , Kirov Ivan , Lui Yvonne , Marmar Charles , Hasanaj Lisena , Serrano Liliana , Al-Kharafi Alhassan , George Allan , Martin Sammie , Riley Edward , Runge William , Cummings Jeffrey L. , Peskind Elaine R. , Colasurdo Elizabeth , Marcus Daniel S. , Gurney Jenny , Greenwald Richard , Johnson Keith A. 
Published: September 2022

Abstract

Purpose
Flourine-18-flortaucipir tau positron emission tomography (PET) was developed for the detection for Alzheimer’s disease. Human imaging studies have begun to investigate its use in chronic traumatic encephalopathy (CTE). Flortaucipir-PET to autopsy correlation studies in CTE are needed for diagnostic validation. We examined the association between end-of-life flortaucipir PET and postmortem neuropathological measurements of CTE-related tau in six former American football players.

Methods
Three former National Football League players and three former college football players who were part of the DIAGNOSE CTE Research Project died and agreed to have their brains donated. The six players had flortaucipir (tau) and florbetapir (amyloid) PET prior to death. All brains from the deceased participants were neuropathologically evaluated for the presence of CTE. On average, the participants were 59.0 (SD = 9.32) years of age at time of PET. PET scans were acquired 20.33 (SD = 13.08) months before their death. Using Spearman correlation analyses, we compared flortaucipir standard uptake value ratios (SUVRs) to digital slide-based AT8 phosphorylated tau (p-tau) density in a priori selected composite cortical, composite limbic, and thalamic regions-of-interest (ROIs).

Results
Four brain donors had autopsy-confirmed CTE, all with high stage disease (n = 3 stage III, n = 1 stage IV). Three of these four met criteria for the clinical syndrome of CTE, known as traumatic encephalopathy syndrome (TES). Two did not have CTE at autopsy and one of these met criteria for TES. Concomitant pathology was only present in one of the non-CTE cases (Lewy body) and one of the CTE cases (motor neuron disease). There was a strong association between flortaucipir SUVRs and p-tau density in the composite cortical (ρ = 0.71) and limbic (ρ = 0.77) ROIs. Although there was a strong association in the thalamic ROI (ρ = 0.83), this is a region with known off-target binding. SUVRs were modest and CTE and non-CTE cases had overlapping SUVRs and discordant p-tau density for some regions.

Conclusions
Flortaucipir-PET could be useful for detecting high stage CTE neuropathology, but specificity to CTE p-tau is uncertain. Off-target flortaucipir binding in the hippocampus and thalamus complicates interpretation of these associations. In vivo biomarkers that can detect the specific p-tau of CTE across the disease continuum are needed.