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Association of probable REM sleep behavior disorder with pathology and years of contact sports play in chronic traumatic encephalopathy

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Abstract

Probable rapid eye movement (REM) sleep behavior disorder (pRBD) is a synucleinopathy-associated parasomnia in which loss of REM sleep muscle atonia results in motor behavior during REM sleep, including dream enactment. Traumatic brain injury is independently associated with increased risk of pRBD and Lewy body disease, and both pRBD and Lewy body disease are often observed in chronic traumatic encephalopathy (CTE). However, the frequency and pathological substrate of pRBD in CTE have not been formally studied and remain unknown. Of the total sample of 247 men, age at death of 63.1 ± 18.8 years (mean ± SD), 80 [32%] were determined by informant report to have symptoms of pRBD. These participants had played more years of contact sports (18.3 ± 11.4) than those without pRBD (15.1 ± 6.5; P = 0.02) and had an increased frequency of Lewy body disease (26/80 [33%] vs 28/167 [17%], P = 0.005). Of the 80 participants with pRBD, 54 [68%] did not have Lewy body disease; these participants were more likely to have neurofibrillary tangles and pretangles in the dorsal and median raphe (41 of 49 [84%] non-LBD participants with pRBD symptoms vs 90 of 136 [66%] non-LBD participants without pRBD symptoms, P = 0.02), brainstem nuclei with sleep regulatory function. Binary logistic regression modeling in the total study sample showed that pRBD in CTE was associated with dorsal and median raphe nuclei neurofibrillary tangles (OR = 3.96, 95% CI [1.43, 10.96], P = 0.008), Lewy body pathology (OR = 2.36, 95% CI [1.18, 4.72], P = 0.02), and years of contact sports participation (OR = 1.04, 95% CI [1.00, 1.08], P = 0.04). Overall, pRBD in CTE is associated with increased years of contact sports participation and may be attributable to Lewy body and brainstem tau pathologies.

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Acknowledgements

We gratefully acknowledge the use of resources and facilities at the Edith Nourse Rogers Memorial Veterans Hospital (Bedford, MA) as well as all the individuals whose participation and contributions made this work possible.

Funding

This work was supported by the Department of Veterans Affairs, Veterans Health Administration, Clinical Sciences Research and Development Merit Award (I01-CX001038); Veterans Affairs Biorepository (BX002466); Alzheimer’s Association (NIRG-305779, NIRG-362697); National Institute of General Medical Sciences (5T32GM007198); National Institute of Aging (RF1AG054156, R56AG057768, RF1AG057768, K23AG046377); National Institute of Neurological Disorders and Stroke (U54NS115266, U01NS086659, K23NS102399); National Institute of Aging Boston University AD Center (P30AG13846; supplement 0572063345-5); Department of Defense Peer Reviewed Alzheimer’s Research Program (PRARP #13267017); and the Concussion Legacy Foundation. This work was also supported by unrestricted gifts from the Andlinger Foundation and WWE.

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Authors and Affiliations

  1. Boston University Alzheimer’s Disease and CTE Center, Boston University School of Medicine, Boston, MA, USA

    Jason W. Adams, Michael L. Alosco, Jesse Mez, Victor E. Alvarez, Bertrand R. Huber, Yorghos Tripodis, Carol Kubilius, Kerry A. Cormier, Rebecca Mathais, Raymond Nicks, Hunter J. Kelley, Nicole Saltiel, Madeline Uretsky, Evan Nair, Nurgul Aytan, Jonathan D. Cherry, Christopher J. Nowinski, Neil W. Kowall, Lee E. Goldstein, Robert A. Stern, Ann C. McKee & Thor D. Stein

  2. Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA, USA

    Jason W. Adams

  3. Department of Neurology, Boston University School of Medicine, Boston, MA, USA

    Michael L. Alosco, Jesse Mez, Victor E. Alvarez, Nurgul Aytan, Jonathan D. Cherry, Neil W. Kowall, Brigid Dwyer, Douglas I. Katz, Robert A. Stern & Ann C. McKee

  4. VA Boston Healthcare System, 150 S. Huntington Avenue, Boston, MA, 02130, USA

    Victor E. Alvarez, Bertrand R. Huber, Kerry A. Cormier, Neil W. Kowall, Ann C. McKee & Thor D. Stein

  5. Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA

    Yorghos Tripodis

  6. Parkinson’s Disease and Movement Disorders Center, Department of Neurology, Mayo Clinic, Scottsdale, AZ, USA

    Charles H. Adler

  7. Department of Veterans Affairs Medical Center, Bedford, MA, USA

    Kerry A. Cormier, Ann C. McKee & Thor D. Stein

  8. Concussion Legacy Foundation, Boston, MA, USA

    Christopher J. Nowinski & Robert C. Cantu

  9. Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA

    Lee E. Goldstein, Ann C. McKee & Thor D. Stein

  10. Brain Injury Program, Braintree Rehabilitation Hospital, Braintree, MA, USA

    Brigid Dwyer & Douglas I. Katz

  11. Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA, USA

    Robert C. Cantu & Robert A. Stern

  12. Department of Neurosurgery, Boston University School of Medicine, Boston, MA, USA

    Robert C. Cantu & Robert A. Stern

  13. Department of Neurosurgery, Emerson Hospital, Concord, MA, USA

    Robert C. Cantu

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Contributions

Study conception and design was led by JWA, MLA, JM, and TDS. The acquisition, analysis, or interpretation of data was performed by JWA, MLA, JM, VEA, BRH, YT, CHA, CK, KAC, RM, RN, HJK, NS, MU, EN, NA, JDC, CJN, NWK, LEG, BD, DIK, RCC, RAS, ACM, and TDS. The manuscript was drafted by JWA, MLA, JM, and TDS. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Thor D. Stein.

Ethics declarations

Conflict of interest

Michael L. Alosco has received honorarium as a Scientific Advisor for Corino Therapeutics, Inc. Dr Goldstein is a paid consultant to Johnson & Johnson, Janssen Research & Development LLC, and Rebiscan Inc, and has received funding from the WWE (World Wrestling Entertainment) and Ivivi Health Sciences. Dr Stern has received research funding from Avid Radiopharmaceuticals Inc, is a member of the Mackey-White Committee of the National Football League Players Association, is a paid consultant to Biogen and Eli Lilly, receives royalties for published neuropsychological tests from Psychological Assessment Resources Inc, and is a member of the Board of Directors of King-Devick Technologies. Dr Cantu is a paid consultant to the National Football League Head Neck and Spine Committee, a vice president and chair of the scientific advisory committee of the National Operating Committee on Standards for Athletic Equipment, and a consultant to the Concussion Legacy Foundation; he also receives royalties from Houghton Mifflin Harcourt and compensation for expert legal opinion to the National Collegiate Athletic Association and National Hockey League and is a member of the Mackey-White Committee of the National Football League Players Association. Dr McKee is a member of the Mackey-White Committee of the National Football League Players Association and reports receiving grants from the National Institutes of Health and Department of Veteran Affairs. Dr Alosco reported grants from National Institutes of Health/National Institute of Neurological Disorders and Stroke during the conduct of the study. Dr Katz reported grants from Boston University School of Medicine Department of Neurology during the conduct of the study. Dr Stern reported grants from the National Institutes of Health during the conduct of the study; personal fees from Biogen and Eli Lilly outside the submitted work; membership on the board of directors for King-Devick Technologies, with stock options; and royalties for published neuropsychological tests from Psychological Assessment Resources Inc. Dr Mez reported grants from the National Institutes of Health, Department of Defense, Alzheimer’s Association, and Concussion Legacy Foundation during the conduct of the study. No other disclosures were reported.

Ethics approval

The study was performed in accordance with the ethical standards established by the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Institutional review board approval was granted from the Boston University Medical Center (BUMC) and the Edith Nourse Rogers Memorial Veterans Hospital, Bedford, MA. The BUMC IRB also granted approval for postmortem clinical record review, neuropathological evaluation, and clinical interviews with donor family members.

Consent to participate

Written consent for brain donation and research participation was provided by donor next-of-kin.

Consent to publish

Not applicable.

Disclaimer

The views, opinions, and/or findings contained in this article are those of the authors and should not be construed as an official Veterans Affairs or Department of Defense position, policy or decision, unless so designated by other official documentation.

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Adams, J.W., Alosco, M.L., Mez, J. et al. Association of probable REM sleep behavior disorder with pathology and years of contact sports play in chronic traumatic encephalopathy. Acta Neuropathol 140, 851–862 (2020). https://doi.org/10.1007/s00401-020-02206-x

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