Janna Kochsiek1,2, Lauren J O'Donnell3,4, Fan Zhang3,4, Elena M Bonke1,2,5, Nico Sollmann1,2,6,7,8, Yorghos Tripodis9,10, Tim L T Wiegand2, David Kaufmann1,2,11,12, Lisa Umminger1,2, Maria A Di Biase1,13, Elisabeth Kaufmann1,2,14, Vivian Schultz1,2,6, Michael L Alosco10,15, Brett M Martin16, Alexander P Lin1,17, Michael J Coleman1, Yogesh Rathi1,4, Ofer Pasternak1,4, Sylvain Bouix1, Robert A Stern10,15,18, Martha E Shenton1,4,13, Inga K Koerte1,2,5,13. 1. Psychiatry Neuroimaging Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. 2. cBRAIN, Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Ludwig-Maximilians-Universität, Munich, Germany. 3. Laboratory of Mathematics in Imaging, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. 4. Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. 5. Graduate School of Systemic Neurosciences, Ludwig-Maximilians-Universität, Munich, Germany. 6. Department of Diagnostic and Interventional Neuroradiology, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. 7. TUM-Neuroimaging Center, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. 8. Department of Diagnostic and Interventional Radiology, University Hospital Ulm, Ulm, Germany. 9. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA. 10. Boston University Alzheimer's Disease Center and Boston University CTE Center, Boston University School of Medicine, Boston, Massachusetts, USA. 11. Department of Radiology, Charité Universitätsmedizin, Berlin, Germany. 12. Department of Radiology, University Hospital Augsburg, University of Augsburg, Germany. 13. Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. 14. Department of Neurology, University Hospital, Ludwig-Maximilians-Universität, Munich, Germany. 15. Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA. 16. Data Coordinating Center, Boston University School of Public Health, Boston, Massachusetts, USA. 17. Center for Clinical Spectroscopy, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. 18. Departments of Neurosurgery and Anatomy & Neurobiology, Boston University School of Medicine, Boston, Massachusetts, USA.
Abstract
BACKGROUND: Exposure to repetitive head impacts (RHI) is associated with an increased risk of later-life neurobehavioral dysregulation and neurodegenerative disease. The underlying pathomechanisms are largely unknown. PURPOSE: To investigate whether RHI exposure is associated with later-life corpus callosum (CC) microstructure and whether CC microstructure is associated with plasma total tau and neuropsychological/neuropsychiatric functioning. STUDY TYPE: Retrospective cohort study. POPULATION: Seventy-five former professional American football players (age 55.2 ± 8.0 years) with cognitive, behavioral, and mood symptoms. FIELD STRENGTH/SEQUENCE: Diffusion-weighted echo-planar MRI at 3 T. ASSESSMENT: Subjects underwent diffusion MRI, venous puncture, neuropsychological testing, and completed self-report measures of neurobehavioral dysregulation. RHI exposure was assessed using the Cumulative Head Impact Index (CHII). Diffusion MRI measures of CC microstructure (i.e., free-water corrected fractional anisotropy (FA), trace, radial diffusivity (RD), and axial diffusivity (AD)) were extracted from seven segments of the CC (CC1-7), using a tractography clustering algorithm. Neuropsychological tests were selected: Trail Making Test Part A (TMT-A) and Part B (TMT-B), Controlled Oral Word Association Test (COWAT), Stroop Interference Test, and the Behavioral Regulation Index (BRI) from the Behavior Rating Inventory of Executive Function, Adult version (BRIEF-A). STATISTICAL TESTS: Diffusion MRI metrics were tested for associations with RHI exposure, plasma total tau, neuropsychological performance, and neurobehavioral dysregulation using generalized linear models for repeated measures. RESULTS: RHI exposure was associated with increased AD of CC1 (correlation coefficient (r) = 0.32, P < 0.05) and with increased plasma total tau (r = 0.34, P < 0.05). AD of the anterior CC1 was associated with increased plasma total tau (CC1: r = 0.30, P < 0.05; CC2: r = 0.29, P < 0.05). Higher trace, AD, and RD of CC1 were associated with better performance (P < 0.05) in TMT-A (trace, r = 0.33; AD, r = 0.31; and RD, r = 0.28) and TMT-B (trace, r = 0.31; RD, r = 0.34). Higher FA and AD of CC2 were associated with better performance (P < 0.05) in TMT-A (FA, r = 0.36; AD, r = 0.28), TMT-B (FA, r = 0.36; AD, r = 0.27), COWAT (FA, r = 0.36; AD, r = 0.32), and BRI (AD, r = 0.29). DATA CONCLUSION: These results suggest an association among RHI exposure, CC microstructure, plasma total tau, and clinical functioning in former professional American football players. LEVEL OF EVIDENCE: 3 Technical Efficacy Stage: 1.
BACKGROUND: Exposure to repetitive head impacts (RHI) is associated with an increased risk of later-life neurobehavioral dysregulation and neurodegenerative disease. The underlying pathomechanisms are largely unknown. PURPOSE: To investigate whether RHI exposure is associated with later-life corpus callosum (CC) microstructure and whether CC microstructure is associated with plasma total tau and neuropsychological/neuropsychiatric functioning. STUDY TYPE: Retrospective cohort study. POPULATION: Seventy-five former professional American football players (age 55.2 ± 8.0 years) with cognitive, behavioral, and mood symptoms. FIELD STRENGTH/SEQUENCE: Diffusion-weighted echo-planar MRI at 3 T. ASSESSMENT: Subjects underwent diffusion MRI, venous puncture, neuropsychological testing, and completed self-report measures of neurobehavioral dysregulation. RHI exposure was assessed using the Cumulative Head Impact Index (CHII). Diffusion MRI measures of CC microstructure (i.e., free-water corrected fractional anisotropy (FA), trace, radial diffusivity (RD), and axial diffusivity (AD)) were extracted from seven segments of the CC (CC1-7), using a tractography clustering algorithm. Neuropsychological tests were selected: Trail Making Test Part A (TMT-A) and Part B (TMT-B), Controlled Oral Word Association Test (COWAT), Stroop Interference Test, and the Behavioral Regulation Index (BRI) from the Behavior Rating Inventory of Executive Function, Adult version (BRIEF-A). STATISTICAL TESTS: Diffusion MRI metrics were tested for associations with RHI exposure, plasma total tau, neuropsychological performance, and neurobehavioral dysregulation using generalized linear models for repeated measures. RESULTS: RHI exposure was associated with increased AD of CC1 (correlation coefficient (r) = 0.32, P < 0.05) and with increased plasma total tau (r = 0.34, P < 0.05). AD of the anterior CC1 was associated with increased plasma total tau (CC1: r = 0.30, P < 0.05; CC2: r = 0.29, P < 0.05). Higher trace, AD, and RD of CC1 were associated with better performance (P < 0.05) in TMT-A (trace, r = 0.33; AD, r = 0.31; and RD, r = 0.28) and TMT-B (trace, r = 0.31; RD, r = 0.34). Higher FA and AD of CC2 were associated with better performance (P < 0.05) in TMT-A (FA, r = 0.36; AD, r = 0.28), TMT-B (FA, r = 0.36; AD, r = 0.27), COWAT (FA, r = 0.36; AD, r = 0.32), and BRI (AD, r = 0.29). DATA CONCLUSION: These results suggest an association among RHI exposure, CC microstructure, plasma total tau, and clinical functioning in former professional American football players. LEVEL OF EVIDENCE: 3 Technical Efficacy Stage: 1.
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