Amyloid PET across the cognitive spectrum in former professional and college American football players: findings from the DIAGNOSE CTE Research Project
Authors: Stern Robert A. , Trujillo-Rodriguez Diana , Tripodis Yorghos , Pulukuri Surya V. , Alosco Michael L. , Adler Charles H. , Balcer Laura J. , Bernick Charles , Baucom Zachary , Marek Kenneth L. , McClean Michael D. , Johnson Keith A. , McKee Ann C. , Stein Thor D. , Mez Jesse , Palmisano Joseph N. , Cummings Jeffrey L. , Shenton Martha E. , Reiman Eric M. ,   for the DIAGNOSE CTE Research Project Investigators, Chen Kewei , Protas Hillary , Su Yi , Boker Connie , Au Rhoda , Cantu Robert C. , Farrer Lindsay , Helm Robert , Katz Douglas I. , Kowall Neil , Mercier Gustavo , Otis James , Weller Jason , Bragg Tahlia , Simkin Irene , van Amerongen Suzan , Andino Alondra , Conneely Shannon , Diamond Courtney , Fagle Tessa , Haller Olivia , Hunt Tennyson , Gullotti Nicole , Kossow Bailey , Kugelmass Carrie , Mariani Megan , Mayville Brian , McLaughlin Kathleen , Nanna Mary , DiPopolo Marty , Platt Taylor , Rice Fiona , Sestak Madison , Annis Douglas , Chaisson Christine , Dixon Diane B. , Finney Carolyn , Gallagher Kerrin , Hartlage Kaitlin , Lu Jun , Martin Brett , Ojo Emmanuel , Pine Brittany , Ramachandran Janani , Tuz-Zahra Fatima , Yhang Eukyung , Bouix Sylvain , Fitzsimmons Jennifer , Lin Alexander P. , Koerte Inga K. , Pasternak Ofer , Arciniega Hector , Billah Tashrif , Bonke Elena , Breedlove Katherine , Carrington Holly , Coello Eduardo , Coleman Michael J. , John Omar , Jung Leonard , Liao Huijun , Loy Maria , Rizzoni Elizabeth , Schultz Vivian , Silva Annelise , Vessey Brynn , Wiegand Tim L. T. , Banks Sarah , Miller Jason , Ritter Aaron , Sabbagh Marwan , de la Cruz Raelynn , Durant Jan , Golceker Morgan , Harmon Nicolette , Kaylegian Jaeson , Long Rachelle , Nance Christin , Sandoval Priscilla , Staples Miranda , Turner Robert W. , Clark Emma F. , Serrano Andrew , Dodick David W. , Geda Yonas , Wethe Jennifer V. , Duffy Amy , Falk Bryce , Howard Marci , Montague Michelle , Osgood Thomas , Babcock Debra , Bellgowan Patrick , Barr William , Goldberg Judith , Joseph Binu , Kirov Ivan , Lui Yvonne , Marmar Charles , Wisniewski Thomas , Al-Kharafi Alhassan , George Allan , Hasanaj Lisena , Martin Sammie , Riley Edward , Runge William , Serrano Liliana , Ashton Nicholas , Zetterberg Henrik , Blennow Kaj , Iliff Jeffrey , Li Gail , Janssen Deidre , Meabon James , Peskind Elaine R. , Piantino Juan , Schindler Abigail , Thomas Ronald , Colasurdo Elizabeth , Shofer Jane , Marcus Daniel S. , Gurney Jenny , Greenwald Richard 
Published: October 2023

Abstract
Background
Exposure to repetitive head impacts (RHI) in American football players can lead to cognitive impairment and dementia due to neurodegenerative disease, particularly chronic traumatic encephalopathy (CTE). The pathognomonic lesion of CTE consists of perivascular aggregates of hyper-phosphorylated tau in neurons at the depths of cortical sulci. However, it is unclear whether exposure to RHI accelerates amyloid-β (Aβ) plaque formation and increases the risk for Alzheimer’s disease (AD). Although the Aβ neuritic plaques characteristic of AD are observed in a minority of later-stage CTE cases, diffuse plaques are more common. This study examined whether former professional and college American football players, including those with cognitive impairment and dementia, have elevated neuritic Aβ plaque density, as measured by florbetapir PET. Regardless of cognitive and functional status, elevated levels of florbetapir uptake were not expected.

Methods
We examined 237 men ages 45–74, including 119 former professional (PRO) and 60 former college (COL) football players, with and without cognitive impairment and dementia, and 58 same-age men without a history of contact sports or TBI (unexposed; UE) and who denied cognitive or behavioral symptoms at telephone screening. Former players were categorized into four diagnostic groups: normal cognition, subjective memory impairment, mild cognitive impairment, and dementia. Positive florbetapir PET was defined by cortical-cerebellar average SUVR of ≥ 1.10. Multivariable linear regression and analysis of covariance (ANCOVA) compared florbetapir average SUVR across diagnostic and exposure groups. Multivariable logistic regression compared florbetapir positivity. Race, education, age, and APOE4 were covariates.

Results
There were no diagnostic group differences either in florbetapir average SUVR or the proportion of elevated florbetapir uptake. Average SUVR means also did not differ between exposure groups: PRO-COL (p = 0.94, 95% C.I. = [− 0.033, 0.025]), PRO-UE (p = 0.40, 95% C.I. = [− 0.010, 0.029]), COL-UE (p = 0.36, 95% CI = [0.0004, 0.039]). Florbetapir was not significantly associated with years of football exposure, cognition, or daily functioning.

Conclusions
Cognitive impairment in former American football players is not associated with PET imaging of neuritic Aβ plaque deposition. These findings are inconsistent with a neuropathological diagnosis of AD in individuals with substantial RHI exposure and have both clinical and medico-legal implications.

Trial registration
NCT02798185.