3 results
4 Risk Factor and Biomarker Correlates of FLAIR White Matter Hyperintensities in Former American Football Players
- Monica T Ly, Fatima Tuz-Zahra, Yorghos Tripodis, Charles H Adler, Laura J Balcer, Charles Bernick, Elaine Peskind, Megan L Mariani, Rhoda Au, Sarah J Banks, William B Barr, Jennifer V Wethe, Mark W Bondi, Lisa Delano-Wood, Robert C Cantu, Michael J Coleman, David W Dodick, Michael D McClean, Jesse Mez, Joseph N Palmisano, Brett Martin, Kaitlin Hartlage, Alexander P Lin, Inga K Koerte, Jeffrey L Cummings, Eric M Reiman, Martha E Shenton, Robert A Stern, Sylvain Bouix, Michael L Alosco
-
- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 608-610
-
- Article
-
- You have access Access
- Export citation
-
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.
A causal roadmap for generating high-quality real-world evidence
- Lauren E. Dang, Susan Gruber, Hana Lee, Issa J. Dahabreh, Elizabeth A. Stuart, Brian D. Williamson, Richard Wyss, Iván Díaz, Debashis Ghosh, Emre Kıcıman, Demissie Alemayehu, Katherine L. Hoffman, Carla Y. Vossen, Raymond A. Huml, Henrik Ravn, Kajsa Kvist, Richard Pratley, Mei-Chiung Shih, Gene Pennello, David Martin, Salina P. Waddy, Charles E. Barr, Mouna Akacha, John B. Buse, Mark van der Laan, Maya Petersen
-
- Journal:
- Journal of Clinical and Translational Science / Volume 7 / Issue 1 / 2023
- Published online by Cambridge University Press:
- 22 September 2023, e212
-
- Article
-
- You have access Access
- Open access
- HTML
- Export citation
-
Increasing emphasis on the use of real-world evidence (RWE) to support clinical policy and regulatory decision-making has led to a proliferation of guidance, advice, and frameworks from regulatory agencies, academia, professional societies, and industry. A broad spectrum of studies use real-world data (RWD) to produce RWE, ranging from randomized trials with outcomes assessed using RWD to fully observational studies. Yet, many proposals for generating RWE lack sufficient detail, and many analyses of RWD suffer from implausible assumptions, other methodological flaws, or inappropriate interpretations. The Causal Roadmap is an explicit, itemized, iterative process that guides investigators to prespecify study design and analysis plans; it addresses a wide range of guidance within a single framework. By supporting the transparent evaluation of causal assumptions and facilitating objective comparisons of design and analysis choices based on prespecified criteria, the Roadmap can help investigators to evaluate the quality of evidence that a given study is likely to produce, specify a study to generate high-quality RWE, and communicate effectively with regulatory agencies and other stakeholders. This paper aims to disseminate and extend the Causal Roadmap framework for use by clinical and translational researchers; three companion papers demonstrate applications of the Causal Roadmap for specific use cases.
Contributors
-
- By Waiel Almoustadi, Brian J. Anderson, David B. Auyong, Michael Avidan, Michael J. Avram, Roland J. Bainton, Jeffrey R. Balser, Juliana Barr, W. Scott Beattie, Manfred Blobner, T. Andrew Bowdle, Walter A. Boyle, Eugene B. Campbell, Laura F. Cavallone, Mario Cibelli, C. Michael Crowder, Ola Dale, M. Frances Davies, Mark Dershwitz, George Despotis, Clifford S. Deutschman, Brian S. Donahue, Marcel E. Durieux, Thomas J. Ebert, Talmage D. Egan, Helge Eilers, E. Wesley Ely, Charles W. Emala, Alex S. Evers, Heidrun Fink, Pierre Foëx, Stuart A. Forman, Helen F. Galley, Josephine M. Garcia-Ferrer, Robert W. Gereau, Tony Gin, David Glick, B. Joseph Guglielmo, Dhanesh K. Gupta, Howard B. Gutstein, Robert G. Hahn, Greg B. Hammer, Brian P. Head, Helen Higham, Laureen Hill, Kirk Hogan, Charles W. Hogue, Christopher G. Hughes, Eric Jacobsohn, Roger A. Johns, Dean R. Jones, Max Kelz, Evan D. Kharasch, Ellen W. King, W. Andrew Kofke, Tom C. Krejcie, Richard M. Langford, H. T. Lee, Isobel Lever, Jerrold H. Levy, J. Lance Lichtor, Larry Lindenbaum, Hung Pin Liu, Geoff Lockwood, Alex Macario, Conan MacDougall, M. B. MacIver, Aman Mahajan, Nándor Marczin, J. A. Jeevendra Martyn, George A. Mashour, Mervyn Maze, Thomas McDowell, Stuart McGrane, Berend Mets, Patrick Meybohm, Charles F. Minto, Jonathan Moss, Mohamed Naguib, Istvan Nagy, Nick Oliver, Paul S. Pagel, Pratik P. Pandharipande, Piyush Patel, Andrew J. Patterson, Robert A. Pearce, Ronald G. Pearl, Misha Perouansky, Kristof Racz, Chinniampalayam Rajamohan, Nilesh Randive, Imre Redai, Stephen Robinson, Richard W. Rosenquist, Carl E. Rosow, Uwe Rudolph, Francis V. Salinas, Robert D. Sanders, Sunita Sastry, Michael Schäfer, Jens Scholz, Thomas W. Schnider, Mark A. Schumacher, John W. Sear, Frédérique S. Servin, Jeffrey H. Silverstein, Tom De Smet, Martin Smith, Joe Henry Steinbach, Markus Steinfath, David F. Stowe, Gary R. Strichartz, Michel M. R. F. Struys, Isao Tsuneyoshi, Robert A. Veselis, Arthur Wallace, Robert P. Walt, David C. Warltier, Nigel R. Webster, Jeanine Wiener-Kronish, Troy Wildes, Paul Wischmeyer, Ling-Gang Wu, Stephen Yang
- Edited by Alex S. Evers, Washington University School of Medicine, St Louis, Mervyn Maze, University of California, San Francisco, Evan D. Kharasch, Washington University School of Medicine, St Louis
-
- Book:
- Anesthetic Pharmacology
- Published online:
- 11 April 2011
- Print publication:
- 10 March 2011, pp viii-xiv
-
- Chapter
- Export citation