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4 Risk Factor and Biomarker Correlates of FLAIR White Matter Hyperintensities in Former American Football Players

Published online by Cambridge University Press:  21 December 2023

Monica T Ly*
Affiliation:
VA San Diego Healthcare System, San Diego, CA, USA. University of California San Diego Health, La Jolla, CA, USA.
Fatima Tuz-Zahra
Affiliation:
Boston University School of Public Health, Boston, MA, USA.
Yorghos Tripodis
Affiliation:
Boston University School of Public Health, Boston, MA, USA. Boston University Alzheimer's Disease Research Center & Chronic Traumatic Encephalopathy Center, Boston, MA, USA.
Charles H Adler
Affiliation:
Mayo Clinic College of Medicine, Scottsdale, AZ, USA.
Laura J Balcer
Affiliation:
NYU Grossman School of Medicine, New York, NY, USA.
Charles Bernick
Affiliation:
Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA. University of Washington, Seattle, WA, USA.
Elaine Peskind
Affiliation:
University of Washington Medicine, Seattle, WA, USA. NW Mental Illness Research, Education, and Clinical Center, Seattle, WA, USA.
Megan L Mariani
Affiliation:
Boston University Alzheimer's Disease Research Center & Chronic Traumatic Encephalopathy Center, Boston, MA, USA.
Rhoda Au
Affiliation:
Boston University School of Public Health, Boston, MA, USA. Boston University Alzheimer's Disease Research Center & Chronic Traumatic Encephalopathy Center, Boston, MA, USA. Framingham Heart Study, Framingham, MA, USA. Slone Epidemiology Center, Boston University, Boston, MA, USA. Boston University School of Medicine, Boston, MA, USA.
Sarah J Banks
Affiliation:
University of California San Diego Health, La Jolla, CA, USA. University of California San Diego, La Jolla, CA, USA.
William B Barr
Affiliation:
NYU Grossman School of Medicine, New York, NY, USA.
Jennifer V Wethe
Affiliation:
Mayo Clinic College of Medicine, Scottsdale, AZ, USA.
Mark W Bondi
Affiliation:
VA San Diego Healthcare System, San Diego, CA, USA. University of California San Diego Health, La Jolla, CA, USA.
Lisa Delano-Wood
Affiliation:
VA San Diego Healthcare System, San Diego, CA, USA. University of California San Diego Health, La Jolla, CA, USA.
Robert C Cantu
Affiliation:
Boston University Alzheimer's Disease Research Center & Chronic Traumatic Encephalopathy Center, Boston, MA, USA.
Michael J Coleman
Affiliation:
Brigham and Women's Hospital, Boston, MA, USA.
David W Dodick
Affiliation:
Mayo Clinic College of Medicine, Scottsdale, AZ, USA.
Michael D McClean
Affiliation:
Boston University School of Public Health, Boston, MA, USA.
Jesse Mez
Affiliation:
Boston University Alzheimer's Disease Research Center & Chronic Traumatic Encephalopathy Center, Boston, MA, USA. Framingham Heart Study, Framingham, MA, USA.
Joseph N Palmisano
Affiliation:
Boston University School of Public Health, Boston, MA, USA.
Brett Martin
Affiliation:
Boston University School of Public Health, Boston, MA, USA.
Kaitlin Hartlage
Affiliation:
Boston University School of Public Health, Boston, MA, USA.
Alexander P Lin
Affiliation:
Brigham and Women's Hospital, Boston, MA, USA.
Inga K Koerte
Affiliation:
VA San Diego Healthcare System, San Diego, CA, USA. Ludwigs-Maximilians-Universität, Munich, Germany.
Jeffrey L Cummings
Affiliation:
University of Nevada Las Vegas, Las Vegas, NV, USA.
Eric M Reiman
Affiliation:
Banner Alzheimer's Institute, Phoenix, AZ, USA. University of Arizona, Phoenix, AZ, USA
Martha E Shenton
Affiliation:
Brigham and Women's Hospital, Boston, MA, USA.
Robert A Stern
Affiliation:
Boston University Alzheimer's Disease Research Center & Chronic Traumatic Encephalopathy Center, Boston, MA, USA. Boston University School of Medicine, Boston, MA, USA.
Sylvain Bouix
Affiliation:
Brigham and Women's Hospital, Boston, MA, USA.
Michael L Alosco
Affiliation:
Boston University Alzheimer's Disease Research Center & Chronic Traumatic Encephalopathy Center, Boston, MA, USA.
*
Correspondence: Monica T. Ly, VA San Diego Healthcare System, San Diego, CA, monica.ly2@va.gov
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Abstract

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Objective:

White matter hyperintensity (WMH) burden is greater, has a frontal-temporal distribution, and is associated with proxies of exposure to repetitive head impacts (RHI) in former American football players. These findings suggest that in the context of RHI, WMH might have unique etiologies that extend beyond those of vascular risk factors and normal aging processes. The objective of this study was to evaluate the correlates of WMH in former elite American football players. We examined markers of amyloid, tau, neurodegeneration, inflammation, axonal injury, and vascular health and their relationships to WMH. A group of age-matched asymptomatic men without a history of RHI was included to determine the specificity of the relationships observed in the former football players.

Participants and Methods:

240 male participants aged 45-74 (60 unexposed asymptomatic men, 60 male former college football players, 120 male former professional football players) underwent semi-structured clinical interviews, magnetic resonance imaging (structural T1, T2 FLAIR, and diffusion tensor imaging), and lumbar puncture to collect cerebrospinal fluid (CSF) biomarkers as part of the DIAGNOSE CTE Research Project. Total WMH lesion volumes (TLV) were estimated using the Lesion Prediction Algorithm from the Lesion Segmentation Toolbox. Structural equation modeling, using Full-Information Maximum Likelihood (FIML) to account for missing values, examined the associations between log-TLV and the following variables: total cortical thickness, whole-brain average fractional anisotropy (FA), CSF amyloid ß42, CSF p-tau181, CSF sTREM2 (a marker of microglial activation), CSF neurofilament light (NfL), and the modified Framingham stroke risk profile (rFSRP). Covariates included age, race, education, APOE z4 carrier status, and evaluation site. Bootstrapped 95% confidence intervals assessed statistical significance. Models were performed separately for football players (college and professional players pooled; n=180) and the unexposed men (n=60). Due to differences in sample size, estimates were compared and were considered different if the percent change in the estimates exceeded 10%.

Results:

In the former football players (mean age=57.2, 34% Black, 29% APOE e4 carrier), reduced cortical thickness (B=-0.25, 95% CI [0.45, -0.08]), lower average FA (B=-0.27, 95% CI [-0.41, -.12]), higher p-tau181 (B=0.17, 95% CI [0.02, 0.43]), and higher rFSRP score (B=0.27, 95% CI [0.08, 0.42]) were associated with greater log-TLV. Compared to the unexposed men, substantial differences in estimates were observed for rFSRP (Bcontrol=0.02, Bfootball=0.27, 994% difference), average FA (Bcontrol=-0.03, Bfootball=-0.27, 802% difference), and p-tau181 (Bcontrol=-0.31, Bfootball=0.17, -155% difference). In the former football players, rFSRP showed a stronger positive association and average FA showed a stronger negative association with WMH compared to unexposed men. The effect of WMH on cortical thickness was similar between the two groups (Bcontrol=-0.27, Bfootball=-0.25, 7% difference).

Conclusions:

These results suggest that the risk factor and biological correlates of WMH differ between former American football players and asymptomatic individuals unexposed to RHI. In addition to vascular risk factors, white matter integrity on DTI showed a stronger relationship with WMH burden in the former football players. FLAIR WMH serves as a promising measure to further investigate the late multifactorial pathologies of RHI.

Type
Poster Session 01: Medical | Neurological Disorders | Neuropsychiatry | Psychopharmacology
Copyright
Copyright © INS. Published by Cambridge University Press, 2023