Study Results
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Basic Information
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ENROLLING_BY_INVITATION
PHASE1
250 participants
INTERVENTIONAL
2020-03-12
2025-12-31
Brief Summary
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Detailed Description
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The investigators propose an in-depth study assessing the association between concussion, sub-concussive exposure, cerebral tau, and clinical outcomes; assessing former NFL players for autoantibodies to cis-tau; assessing carbon monoxide (CO), memantine, environmental enrichment (EE), and cis P-tau antibodies for preventing and treating neurologic sequela of rmTBI. The most promising treatment(s) from preclinical studies will ultimately be translated into clinical trials for individuals identified during the clinical study who are at risk for long-term neurologic health problems. The study will be carried out at 2 sites, The University of North Carolina at Chapel Hill and The Medical College of Wisconsin both at the oversight of the main grant awardee, Boston Children's Hospital.
In order to prospectively and longitudinally track progression of neurologic health and assess associations with concussion and sub-concussive exposure the investigators plan to execute multiple study phases: (1) Former National Football League (NFL) Players will complete the General Health Survey (GHS)(part of a previous research study); (2) Stratification based on age and the GHS; (3) Phone Screening with Brief Test of Adult Cognition by Telephone (BTACT); (4) Re-stratification based on BTACT scores; (5) In-Person Neurobiopsychosocial Research Evaluation 1; (6) Annual Follow-Up Health Surveys; and (7) In-Person Neurobiopsychosocial Research Evaluation 2.
Based on the stratification above, 250 subjects will be enrolled for In-Person Research Evaluation 1. This cohort will include 100 high cognitive functioning former NFL players, 100 low cognitive functioning former NFL players, and a group of 50 demographically matched healthy controls. Informants of the former NFL subjects, that are selected for In-Person Research Evaluation 1, will also be asked to complete a series of informant-based questionnaires (n=200). Subjects enrolled in the In-Person Research Evaluation 1 will complete an assessment of neurobiopsychosocial function, to include a detailed neuropsychological assessment, patient-reported outcomes, and symptom validity measures. Assessment of neurobiopsychosocial function will also include proteomic and genomic studies, multi-modal magnetic resonance imaging (MRI) and position emission tomography (PET) molecular imaging studies of tau, amyloid and inflammation.
Annual follow-up surveys of health status and life function (selected repeat measures from the GHS) will be sent/administered annually for 5 years. Based upon the annual follow-up survey of health status and life function, a subset of former NFL players and all controls will return for second a research assessment of neurobiopsychosocial function that mirrors the in-person research evaluation.
Conditions
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Study Design
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NON_RANDOMIZED
PARALLEL
BASIC_SCIENCE
NONE
Study Groups
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Low Cognitive Functioning/Low Concussion History
Former NFL players with low cognitive function and low concussion history will be included in this group.
[11C] PiB
Per study protocol static PET images will be acquired after IV infusion of CPiB to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.
[18F] PBR111
Per study protocol static PET images will be acquired after IV infusion of F-PBR111 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.
[18F] Flortaucipir
Per study protocol static PET images will be acquired after IV infusion of F-T807 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.
High Cognitive Functioning/ High Concussion History
Former NFL players with high cognitive function and high concussion history will be included in this group.
[11C] PiB
Per study protocol static PET images will be acquired after IV infusion of CPiB to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.
[18F] PBR111
Per study protocol static PET images will be acquired after IV infusion of F-PBR111 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.
[18F] Flortaucipir
Per study protocol static PET images will be acquired after IV infusion of F-T807 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.
Low Cognitive Functioning/High Concussion History
Former NFL players with low cognitive function and high concussion history will be included in this group.
[11C] PiB
Per study protocol static PET images will be acquired after IV infusion of CPiB to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.
[18F] PBR111
Per study protocol static PET images will be acquired after IV infusion of F-PBR111 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.
[18F] Flortaucipir
Per study protocol static PET images will be acquired after IV infusion of F-T807 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.
High Cognitive Functioning/Low Concussion History
Former NFL players with high cognitive function and low concussion history will be included in this group.
[11C] PiB
Per study protocol static PET images will be acquired after IV infusion of CPiB to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.
[18F] PBR111
Per study protocol static PET images will be acquired after IV infusion of F-PBR111 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.
[18F] Flortaucipir
Per study protocol static PET images will be acquired after IV infusion of F-T807 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.
Healthy Male Controls
Healthy male demographically matched controls will be included in this group.
[11C] PiB
Per study protocol static PET images will be acquired after IV infusion of CPiB to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.
[18F] PBR111
Per study protocol static PET images will be acquired after IV infusion of F-PBR111 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.
[18F] Flortaucipir
Per study protocol static PET images will be acquired after IV infusion of F-T807 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.
Low Cognitive Functioning/Medium Concussion History
Former NFL players with low cognitive function and medium concussion history will be included in this group.
[11C] PiB
Per study protocol static PET images will be acquired after IV infusion of CPiB to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.
[18F] PBR111
Per study protocol static PET images will be acquired after IV infusion of F-PBR111 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.
[18F] Flortaucipir
Per study protocol static PET images will be acquired after IV infusion of F-T807 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.
Medium Cognitive Functioning/Low Concussion History
Former NFL Players with medium cognitive functioning and low concussion history with be included in this group.
[11C] PiB
Per study protocol static PET images will be acquired after IV infusion of CPiB to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.
[18F] PBR111
Per study protocol static PET images will be acquired after IV infusion of F-PBR111 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.
[18F] Flortaucipir
Per study protocol static PET images will be acquired after IV infusion of F-T807 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.
Medium Cognitive Functioning/Medium Concussion History
Former NFL Players with medium cognitive functioning and medium concussion history with be included in this group.
[11C] PiB
Per study protocol static PET images will be acquired after IV infusion of CPiB to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.
[18F] PBR111
Per study protocol static PET images will be acquired after IV infusion of F-PBR111 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.
[18F] Flortaucipir
Per study protocol static PET images will be acquired after IV infusion of F-T807 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.
Medium Cognitive Functioning/High Concussion History
Former NFL Players with medium cognitive functioning and high concussion history with be included in this group.
[11C] PiB
Per study protocol static PET images will be acquired after IV infusion of CPiB to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.
[18F] PBR111
Per study protocol static PET images will be acquired after IV infusion of F-PBR111 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.
[18F] Flortaucipir
Per study protocol static PET images will be acquired after IV infusion of F-T807 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.
High Cognitive Functioning/Medium Concussion History
Former NFL Players with high cognitive functioning and high concussion history with be included in this group.
[11C] PiB
Per study protocol static PET images will be acquired after IV infusion of CPiB to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.
[18F] PBR111
Per study protocol static PET images will be acquired after IV infusion of F-PBR111 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.
[18F] Flortaucipir
Per study protocol static PET images will be acquired after IV infusion of F-T807 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.
Interventions
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[11C] PiB
Per study protocol static PET images will be acquired after IV infusion of CPiB to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.
[18F] PBR111
Per study protocol static PET images will be acquired after IV infusion of F-PBR111 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.
[18F] Flortaucipir
Per study protocol static PET images will be acquired after IV infusion of F-T807 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Retired from professional football
* Ages between 50-70
* No prior exposure to football, collision sports, or prior concussions
* They will be matched to former NFL players by age and estimated premorbid intellectual functioning.
* Ages between 50-70
Exclusion Criteria
* History of Moderate or Severe TBI
* Current primary Axis I diagnosis of Psychotic Disorder
* History or clinical suspicion of other conditions (e.g., epilepsy, stroke, dementia) known to cause cognitive dysfunction
* Diagnosis /associated treatment that would preclude participation in full study protocol (e.g., terminal cancer)
50 Years
70 Years
MALE
Yes
Sponsors
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Boston Children's Hospital
OTHER
Medical College of Wisconsin
OTHER
National Football League
OTHER
University of North Carolina, Chapel Hill
OTHER
Responsible Party
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Principal Investigators
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William Meehan, MD
Role: PRINCIPAL_INVESTIGATOR
Boston Children's Hospital
Michael McCrea, PhD
Role: PRINCIPAL_INVESTIGATOR
Medical College of Wisconsin
Jason Mihalik, PhD
Role: PRINCIPAL_INVESTIGATOR
University of North Carolina, Chapel Hill
Locations
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Boston Children's Hospital
Waltham, Massachusetts, United States
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States
Medical College of Wisconsin
Milwaukee, Wisconsin, United States
Countries
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References
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Randolph C, Karantzoulis S, Guskiewicz K. Prevalence and characterization of mild cognitive impairment in retired national football league players. J Int Neuropsychol Soc. 2013 Sep;19(8):873-80. doi: 10.1017/S1355617713000805. Epub 2013 Aug 1.
Guskiewicz KM, Marshall SW, Bailes J, McCrea M, Cantu RC, Randolph C, Jordan BD. Association between recurrent concussion and late-life cognitive impairment in retired professional football players. Neurosurgery. 2005 Oct;57(4):719-26; discussion 719-26. doi: 10.1093/neurosurgery/57.4.719.
Kerr ZY, Marshall SW, Harding HP Jr, Guskiewicz KM. Nine-year risk of depression diagnosis increases with increasing self-reported concussions in retired professional football players. Am J Sports Med. 2012 Oct;40(10):2206-12. doi: 10.1177/0363546512456193. Epub 2012 Aug 24.
Clark MD, Varangis EML, Champagne AA, Giovanello KS, Shi F, Kerr ZY, Smith JK, Guskiewicz KM. Effects of Career Duration, Concussion History, and Playing Position on White Matter Microstructure and Functional Neural Recruitment in Former College and Professional Football Athletes. Radiology. 2018 Mar;286(3):967-977. doi: 10.1148/radiol.2017170539. Epub 2017 Oct 31.
Meehan WP 3rd, Taylor AM, Berkner P, Sandstrom NJ, Peluso MW, Kurtz MM, Pascual-Leone A, Mannix R. Division III Collision Sports Are Not Associated with Neurobehavioral Quality of Life. J Neurotrauma. 2016 Jan 15;33(2):254-9. doi: 10.1089/neu.2015.3930. Epub 2015 Jul 20.
Mannix R, Meehan WP 3rd, Pascual-Leone A. Sports-related concussions - media, science and policy. Nat Rev Neurol. 2016 Aug;12(8):486-90. doi: 10.1038/nrneurol.2016.99. Epub 2016 Jul 1.
Carson A. Concussion, dementia and CTE: are we getting it very wrong? J Neurol Neurosurg Psychiatry. 2017 Jun;88(6):462-464. doi: 10.1136/jnnp-2016-315510. Epub 2017 Apr 10. No abstract available.
Meehan W 3rd, Mannix R, Zafonte R, Pascual-Leone A. Chronic traumatic encephalopathy and athletes. Neurology. 2015 Oct 27;85(17):1504-11. doi: 10.1212/WNL.0000000000001893. Epub 2015 Aug 7.
Deshpande SK, Hasegawa RB, Rabinowitz AR, Whyte J, Roan CL, Tabatabaei A, Baiocchi M, Karlawish JH, Master CL, Small DS. Association of Playing High School Football With Cognition and Mental Health Later in Life. JAMA Neurol. 2017 Aug 1;74(8):909-918. doi: 10.1001/jamaneurol.2017.1317.
Baugh CM, Kroshus E, Kiernan PT, Mendel D, Meehan WP 3rd. Football Players' Perceptions of Future Risk of Concussion and Concussion-Related Health Outcomes. J Neurotrauma. 2017 Feb 15;34(4):790-797. doi: 10.1089/neu.2016.4585. Epub 2016 Sep 16.
Zemlan FP, Jauch EC, Mulchahey JJ, Gabbita SP, Rosenberg WS, Speciale SG, Zuccarello M. C-tau biomarker of neuronal damage in severe brain injured patients: association with elevated intracranial pressure and clinical outcome. Brain Res. 2002 Aug 23;947(1):131-9. doi: 10.1016/s0006-8993(02)02920-7.
Van Essen DC, Smith SM, Barch DM, Behrens TE, Yacoub E, Ugurbil K; WU-Minn HCP Consortium. The WU-Minn Human Connectome Project: an overview. Neuroimage. 2013 Oct 15;80:62-79. doi: 10.1016/j.neuroimage.2013.05.041. Epub 2013 May 16.
Smith SM, Beckmann CF, Andersson J, Auerbach EJ, Bijsterbosch J, Douaud G, Duff E, Feinberg DA, Griffanti L, Harms MP, Kelly M, Laumann T, Miller KL, Moeller S, Petersen S, Power J, Salimi-Khorshidi G, Snyder AZ, Vu AT, Woolrich MW, Xu J, Yacoub E, Ugurbil K, Van Essen DC, Glasser MF; WU-Minn HCP Consortium. Resting-state fMRI in the Human Connectome Project. Neuroimage. 2013 Oct 15;80:144-68. doi: 10.1016/j.neuroimage.2013.05.039. Epub 2013 May 20.
Glasser MF, Sotiropoulos SN, Wilson JA, Coalson TS, Fischl B, Andersson JL, Xu J, Jbabdi S, Webster M, Polimeni JR, Van Essen DC, Jenkinson M; WU-Minn HCP Consortium. The minimal preprocessing pipelines for the Human Connectome Project. Neuroimage. 2013 Oct 15;80:105-24. doi: 10.1016/j.neuroimage.2013.04.127. Epub 2013 May 11.
Hampshire A, MacDonald A, Owen AM. Hypoconnectivity and hyperfrontality in retired American football players. Sci Rep. 2013 Oct 17;3:2972. doi: 10.1038/srep02972.
Kaushal M, Espana LY, Nencka AS, Wang Y, Nelson LD, McCrea MA, Meier TB. Resting-state functional connectivity after concussion is associated with clinical recovery. Hum Brain Mapp. 2019 Mar;40(4):1211-1220. doi: 10.1002/hbm.24440. Epub 2018 Nov 19.
Other Identifiers
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19-1065
Identifier Type: -
Identifier Source: org_study_id
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