Association of Vascular Risk Factors and CSF and Imaging Biomarkers With White Matter Hyperintensities in Former
Monica T Ly1, Fatima Tuz-Zahra1, Yorghos Tripodis1
1From the VA San Diego Healthcare System (M.T.L., M.W.B., L.M.D.-W.), CA; Department of Psychiatry (M.T.L., S.J.B., M.W.B., L.M.D.-W.), University of California San Diego Health, La Jolla; Departments of Biostatistics (F.T.-Z., Y.T.), Epidemiology (R.A.), Environmental Health (M.D.M.), Biostatistics and Epidemiology Data Analytics Center (J.P., B.M., K.H.), Boston University School of Public Health, MA; Boston University Alzheimer's Disease Research Center (Y.T., J.B.M., M.L.A., R.A., R.C.C., R.A.S.), Boston University CTE Center; Department of Neurology, Boston University Chobanian & Avedisian School of Medicine; Departments of Neurology (C.H.A., D.W.D.) and Psychiatry and Psychology (J.V.W.), Mayo Clinic School of Medicine, Mayo Clinic Arizona, Scottsdale; Departments of Neurology (L.J.B.), Population Health and Ophthalmology, (L.J.B.), and Neurology (W.B.B.), NYU Grossman School of Medicine; Cleveland Clinic Lou Ruvo Center for Brain Health (C.B.), Las Vegas, NV; Department of Neurology (C.B.), University of Washington, Seattle; Department of Neurodegenerative Disease (H.Z.), and UK Dementia Research Institute (H.Z.), University College London Institute of Neurology, UK; Hong Kong Center for Neurodegenerative Diseases (H.Z.), China; Wisconsin Alzheimer's Disease Research Center (H.Z.), University of Wisconsin-Madison; Clinical Neurochemistry Laboratory (H.Z., K.B.), Sahlgrenska University Hospital, Gothenburg; Department of Psychiatry and Neurochemistry (K.B.), Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sweden; VA Northwest Mental Illness Research, Education, and Clinical Center (E.R.P.), Seattle, WA; Department of Psychiatry and Behavioral Sciences (E.R.P.), University of Washington School of Medicine, Seattle; Framingham Heart Study (R.A., J.B.M.); Slone Epidemiology Center (R.A.), Boston University, MA; Department of Neurosciences (S.J.B.), University of California San Diego; Psychiatry Neuroimaging Laboratory (M.J.C., A.P.L., I.K.K., M.E.S., S.B.), Departments of Psychiatry Radiology (M.E.S.), and Center for Clinical Spectroscopy (A.P.L.), Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; cBRAIN (I.K.K.), Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, Ludwigs-Maximilians-Universität, Munich, Germany; Chambers-Grundy Center for Transformative Neuroscience (J.L.C.), Department of Brain Health, School of Integrated Health Sciences, University of Nevada Las Vegas; Banner Alzheimer's Institute (E.M.R.), Phoenix; Department of Psychiatry (E.M.R.), University of Arizona, Phoenix; Arizona State University (E.M.R.), Phoenix; Translational Genomics Research Institute (E.M.R.), Phoenix; Arizona Alzheimer's Consortium (E.M.R.), Phoenix; and Department of Software Engineering and Information Technology (S.B.), École de technologie supérieure, Université du Québec, Montréal, Canada.
Background And Objectives:
Recent data link exposure to repetitive head impacts (RHIs) from American football with increased white matter hyperintensity (WMH) burden. WMH might have unique characteristics in the context of RHI beyond vascular risk and normal aging processes. We evaluated biological correlates of WMH in former American football players, including markers of amyloid, tau, inflammation, axonal injury, neurodegeneration, and vascular health.
Methods:
Participants underwent clinical interviews, MRI, and lumbar puncture as part of the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy Research Project. Structural equation modeling tested direct and indirect effects between log-transformed total fluid-attenuated inversion recovery (FLAIR) lesion volumes (TLV) and the revised Framingham stroke risk profile (rFSRP), MRI-derived global metrics of cortical thickness and fractional anisotropy (FA), and CSF levels of amyloid β1-42, p-tau181, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and neurofilament light. Covariates included age, race, education, body mass index, APOE ε4 carrier status, and evaluation site. Models were performed separately for former football players and a control group of asymptomatic men unexposed to RHI.
Results:
In 180 former football players (mean age = 57.2, 36% Black), higher log(TLV) had direct associations with the following: higher rFSRP score (B = 0.26, 95% CI 0.07-0.40), higher p-tau181 (B = 0.17, 95% CI 0.01-0.43), lower FA (B = -0.28, 95% CI -0.42 to -0.13), and reduced cortical thickness (B = -0.25, 95% CI -0.45 to -0.08). In 60 asymptomatic unexposed men (mean age = 59.3, 40% Black), there were no direct effects on log(TLV) (rFSRP: B = -0.03, 95% CI -0.48 to 0.57; p-tau181: B = -0.30, 95% CI -1.14 to 0.37; FA: B = -0.07, 95% CI -0.48 to 0.42; or cortical thickness: B = -0.28, 95% CI -0.64 to 0.10). The former football players showed stronger associations between log(TLV) and rFSRP (1,069% difference in estimates), p-tau181 (158%), and FA (287%) than the unexposed men.
Discussion:
Risk factors and biological correlates of WMH differed between former American football players and asymptomatic unexposed men. In addition to vascular health, p-tau181 and diffusion tensor imaging indices of white matter integrity showed stronger associations with WMH in the former football players. FLAIR WMH may have specific risk factors and pathologic underpinnings in RHI-exposed individuals.
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