. 2024 Jan 23;102(2):e208030.

doi: 10.1212/WNL.0000000000208030. Epub 2023 Dec 20.

Association of Vascular Risk Factors and CSF and Imaging Biomarkers With White Matter Hyperintensities in Former American Football Players

Monica T Ly¹, Fatima Tuz-Zahra¹, Yorghos Tripodis¹, Charles H Adler¹, Laura J Balcer¹, Charles Bernick¹, Henrik Zetterberg¹, Kaj Blennow¹, Elaine R Peskind¹, Rhoda Au¹, Sarah J Banks¹, William B Barr¹, Jennifer V Wethe¹, Mark W Bondi¹, Lisa M Delano-Wood¹, Robert C Cantu¹, Michael J Coleman¹, David W Dodick¹, Michael D McClean¹, Jesse B Mez¹, Joseph Palmisano¹, Brett Martin¹, Kaitlin Hartlage¹, Alexander P Lin¹, Inga K Koerte¹, Jeffrey L Cummings¹, Eric M Reiman¹, Martha E Shenton¹, Robert A Stern¹, Sylvain Bouix¹, Michael L Alosco¹; for DIAGNOSE CTE Research Project¹

Collaborators, Affiliations

Collaborators

for DIAGNOSE CTE Research Project:
Yi Su, Kewei Chen, Hillary Protas, Connie Boker, Lindsay Farrer, Robert Helm, Douglas I Katz, Neil Kowall, Ann C McKee, Gustavo Mercier, James Otis, Jason Weller, Irene Simkin, Alondra Andino, Shannon Conneely, Courtney Diamond, Tessa Fagle, Olivia Haller, Tennyson Hunt, Nicole Gullotti, Megan Mariani, Brian Mayville, Kathleen McLaughlin, Mary Nanna, Taylor Platt, Surya Pulukuri, Fiona Rice, Madison Sestak, Douglas Annis, Christine Chaisson, Diane B Dixon, Carolyn Finney, Kerrin Gallagher, Jun Lu, Emmanuel Ojo, Brittany Pine, Janani Ramachandran, Jennifer Fitzsimmons, Ofer Pasternak, Hector Arciniega, Tashrif Billah, Elena M Bonke, Katherine Breedlove, Eduardo Coello, Leonard B Jung, Huijun Liao, Maria Loy, Elizabeth Rizzoni, Vivian Schultz, Annelise Silva, Brynn Vessey, Lim LT Wiegand, Jason Miller, Aaron Ritter, Marwan Sabbagh, Raelynn de la Cruz, Jan Durant, Morgan Golceker, Nicolette Harmon, Kaeson Kaylegian, Rachelle Long, Christin Nance, Priscilla Sandoval, Robert W Turner, Kenneth L Marek, Andrew Serrano, Yonas Geda, Bryce Falk, Amy Duffy, Marci Howard, Michelle Montague, Thomas Osgood, Debra Babcock, Patrick Bellgowan, Judith Goldberg, Thomas Wisniewski, Ivan Kirov, Yvonne Lui, Charles Marmar, Lisena Hasanaj, Liliana Serrano, Alhassan Al-Kharafi, Allan George, Sammie Martin, Edward Riley, William Runge, Elizabeth Colasurdo, Daniel S Marcus, Jenny Gurney, Richard Greenwald, Keith A Johnson

Affiliation

¹ From 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.

PMID: 38165330
PMCID: PMC10870736
DOI: 10.1212/WNL.0000000000208030

Association of Vascular Risk Factors and CSF and Imaging Biomarkers With White Matter Hyperintensities in Former American Football Players

Monica T Ly et al. Neurology. 2024.

. 2024 Jan 23;102(2):e208030.

doi: 10.1212/WNL.0000000000208030. Epub 2023 Dec 20.

Authors

Collaborators

for DIAGNOSE CTE Research Project:
Yi Su, Kewei Chen, Hillary Protas, Connie Boker, Lindsay Farrer, Robert Helm, Douglas I Katz, Neil Kowall, Ann C McKee, Gustavo Mercier, James Otis, Jason Weller, Irene Simkin, Alondra Andino, Shannon Conneely, Courtney Diamond, Tessa Fagle, Olivia Haller, Tennyson Hunt, Nicole Gullotti, Megan Mariani, Brian Mayville, Kathleen McLaughlin, Mary Nanna, Taylor Platt, Surya Pulukuri, Fiona Rice, Madison Sestak, Douglas Annis, Christine Chaisson, Diane B Dixon, Carolyn Finney, Kerrin Gallagher, Jun Lu, Emmanuel Ojo, Brittany Pine, Janani Ramachandran, Jennifer Fitzsimmons, Ofer Pasternak, Hector Arciniega, Tashrif Billah, Elena M Bonke, Katherine Breedlove, Eduardo Coello, Leonard B Jung, Huijun Liao, Maria Loy, Elizabeth Rizzoni, Vivian Schultz, Annelise Silva, Brynn Vessey, Lim LT Wiegand, Jason Miller, Aaron Ritter, Marwan Sabbagh, Raelynn de la Cruz, Jan Durant, Morgan Golceker, Nicolette Harmon, Kaeson Kaylegian, Rachelle Long, Christin Nance, Priscilla Sandoval, Robert W Turner, Kenneth L Marek, Andrew Serrano, Yonas Geda, Bryce Falk, Amy Duffy, Marci Howard, Michelle Montague, Thomas Osgood, Debra Babcock, Patrick Bellgowan, Judith Goldberg, Thomas Wisniewski, Ivan Kirov, Yvonne Lui, Charles Marmar, Lisena Hasanaj, Liliana Serrano, Alhassan Al-Kharafi, Allan George, Sammie Martin, Edward Riley, William Runge, Elizabeth Colasurdo, Daniel S Marcus, Jenny Gurney, Richard Greenwald, Keith A Johnson

Affiliation

¹ From 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.

PMID: 38165330
PMCID: PMC10870736
DOI: 10.1212/WNL.0000000000208030

Abstract

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 β_1-42, 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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Conflict of interest statement

M.T. Ly, F. Tuz-Zahra, and Y. Tripodis report no disclosures relevant to the manuscript. C.H. Adler consulted for Avion, CND Life Sciences, Jazz, and Precon Health. L.J. Balcer is Editor-in-Chief of the Journal of Neuro-Ophthalmology, and is a paid consultant to Biogen (Cambridge, MA). C. Bernick receives research support from the Ultimate Fighting Championship, Top Rank promotions, Haymon Boxing, Las Vegas Raiders, and Professional Bull Riders, and is a paid consultant for Aurora Concussion Therapy Systems, Inc. (St. Paul, MN). H. Zetterberg has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). K. Blennow reports no disclosures relevant to the manuscript. E.R. Peskind serves on the Scientific Advisory Boards of Acadia and Avanir, and on a Data Monitoring Committee for Eli Lilly. R. Au is a paid consultant to Biogen (Cambridge, MA) and serves on the Scientific Advisory Board of Signant Health (Blue Bell, PA). W.B. Barr provides expert witness testimony in legal cases involving concussion and CTE. J.V. Wethe reports a financial interest in Mayo Clinic Concussion Check, which incorporates the King-Devick Test in association with Mayo Clinic. M.W. Bondi and L. Delano-Wood report no disclosures relevant to the manuscript. R.C. Cantu is a Senior Advisor to the NFL Head Neck & Spine Committee; Vice President, National Operating Committee on Standards for Athletic Equipment; and Chair, Scientific Advisory Committee, Co-Founder, and Medical Director, Concussion Legacy Foundation. He is a member of the Medical Science Committee for the National Collegiate Athletic Association Student-Athlete Concussion Injury Litigation, and he receives royalties for published books from Houghton Mifflin Harcourt. M.J. Coleman reports no disclosures relevant to the manuscript. D.W. Dodick served as consultant for: Amgen, Atria, Cerecin, Cooltech, Ctrl M, Allergan, Biohaven, GSK, Lundbeck, Eli Lilly, Novartis, Impel, Satsuma, Theranica, WL Gore, Nocira, Perfood, Praxis, AYYA Biosciences, and Revance, received honoraria from: Vector psychometric Group, Clinical Care Solutions, CME Outfitters, Curry Rockefeller Group, DeepBench, Global Access Meetings, KLJ Associates, Academy for Continued Healthcare Learning, Majallin LLC, Medlogix Communications, MJH Lifesciences, Miller Medical Communications, WebMD Health/Medscape, Wolters Kluwer, Oxford University Press, and Cambridge University Press, holds stock options/shareholder/patents/board of directors in: Ctrl M (options), Aural analytics (options), ExSano (options), Palion (options), Healint (Options), Theranica (Options), Second Opinion/Mobile Health (Options), Epien (Options/Board), Nocira (options), Matterhorn (Shares/Board), Ontologics (Shares/Board), King-Devick Technologies (Options/Board), Precon Health (Options/Board), AYYA Biosciences (Options), Patent 17189376.1-1466:vTitle: Botulinum Toxin Dosage Regimen for Chronic Migraine Prophylaxis, and received research support from: Department of Defense, NIH, Henry Jackson Foundation, Sperling Foundation, American Migraine Foundation, Patient Centered Outcomes Research Institute (PCORI). M.D. McClean, J. Mez, J.N. Palmisano, B. Martin, and K. Hartlage report no disclosures relevant to the manuscript. A.P. Lin is a paid consultant to Agios Pharmaceuticals (Cambridge, MA), Biomarin Pharmaceuticals (Novato, CA), and Moncton MRI (Moncton, Canada). He is the co-founder of BrainSpec, Inc. I.K. Koerte reports no disclosures relevant to the manuscript. J.L. Cummings has provided consultation to Acadia, Alkahest, AriBio, Avanir, Axsome, Behren Therapeutics, Biogen, Cassava, Cerecin, Cerevel, Cortexyme, EIP Pharma, Eisai, GemVax, Genentech, Green Valley, Grifols, Janssen, Jazz, Karuna, Merck, Novo Nordisk, Otsuka, ReMYND, Resverlogix, Roche, Samumed, Samus, Signant Health, Sunovion, Suven, United Neuroscience, and Unlearn AI pharmaceutical and assessment companies. He owns the copyright of the Neuropsychiatric Inventory. E.M. Reiman is a compensated scientific advisor for Alkahest, Alzheon, Aural Analytics, Denali, Green Valley, Retromer Therapeutics, and Vaxxinity, and a co-founder of ALZPath. M.E. Shenton reports no disclosures relevant to the manuscript. R.A. Stern is a member of the Board of Directors of King-Devick Technologies, Inc. (Chicago, IL), and he receives royalties for published neuropsychological tests from Psychological Assessment Resources, Inc. (Lutz, FL). S. Bouix and M.L. Alosco report no disclosures relevant to the manuscript. Go to Neurology.org/N for full disclosures.

Figures

**Figure 1. SEM of Direct and Indirect Effects on WMH**
Bolded lines indicate significant associations, and dashed lines indicate nonsignificant associations in the former football players. FA = fractional anisotropy; LH = left hemisphere; NfL = neurofilament light; rFSRP = revised Framingham stroke risk profile; RH = right hemisphere; SEM = structural equation modeling; sTREM2 = soluble triggering receptor expressed on myeloid cells 2; TLV = total lesion volume; WMH = white matter hyperintensity.

**Figure 2. Associations Between WMHs (log[TLV]) and (A) rFSRP; (B) CSF p-tau₁₈₁; (C) Average FA; and (D) Average Cortical Thickness**
x-Axes show the predictor variable and y-axes the response variable according to hypothesized SEM pathways shown in Figure 1. Bands show 95% CIs. FA = fractional anisotropy; rFSRP = revised Framingham stroke risk profile; SEM = structural equation modeling; TLV = total lesion volume; WMH = white matter hyperintensity.

See this image and copyright information in PMC

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Association of Vascular Risk Factors and CSF and Imaging Biomarkers With White Matter Hyperintensities in Former American Football Players

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Association of Vascular Risk Factors and CSF and Imaging Biomarkers With White Matter Hyperintensities in Former American Football Players

Authors

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Abstract

Conflict of interest statement

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