BU Medical Research Plan

Updated: February 1, 2019

 

Boston University (BU) Investigators

 

Principal Investigator:

Robert A. Stern, PhD, Professor of Neurology, Neurosurgery, and Anatomy &

Neurobiology; Clinical Core Director, BU Alzheimer’s Disease Center (ADC);

Director of Clinical Research, BU CTE Center; Boston University School of

Medicine (BUSM)

 

Co-Principal Investigator:

Michael L. Alosco, PhD, Assistant Professor of Neurology; Investigator, BU ADC and BU

CTE Center; BUSM;

 

Investigator and Study Neurologist:

Jesse Mez, MD, MS, Assistant Professor of Neurology; Clinical Core Associate Director,

BU ADC; Investigator, BU CTE Center; BUSM

 

Biostatistician and Co-investigator:

Yorghos Tripodis, PhD, Research Associate Professor of Biostatistics, BU School of

Public Health (SPH); Data Management and Biostatistics Core Director, BU

ADC; Investigator, BU CTE Center; BUSM

 

This Project Is Being Conducted In Partnership With The Independent

Notre Dame Footballers  Medical Research  Project

 

Players Steering Committee Co-Chairs:

Rocky Bleier, RB #28, ND ’68

David Casper, TE #86, ND ‘74

Vagas Ferguson, RB #32, ND ’80

 

Project Coordinators:

Edward Ziegler, RB #32, ND ’70

Bill Etter, QB #2, ND ’72

Drew Mahalic, LB #45, ND ’75

Pat Sarb, CB #29, ‘ND ’76

Terry Eurick, RB #40, ND ’78

David Condeni, SE #80, ND ’81

 

 

Media Liaison:

Tom Clements, QB #2, ND ’75

Bob Belden, QB #2, ND ‘

John McHale, LB #43, ND ‘71

Luther Bradley, DB #78, ND ‘77

 

Fund Raising:

Tom Sullivan, OT #55, ND ‘66

George Geoddeke, C #64, ND ’67

Steve Orsini, FB #14, ND’78

Gene Smith, LB #90, ND ’77

 

Players Physicians Committee:

John Cieszkowski MD, FB #35, ND ‘72

Jim Sheahan MD, DB #16, ND ’71

Max Walsh MD, OT #57, ND ’74

Jim Ryan MD, HB/K #11, ND 1967

 

Players Participation and Support Committee:

Ross Browner, DE #89, ND ’78

Walt Patulski, DE #82, ND ’72

Luther Bradley, CB #20, ND ’77

Mike Townsend, DHB #27, ND ’74

Mike McCoy, DT #77, ND ’70

George Kunz, OT #78, ND ’69

 

Scientific and Medical Advisors to Steering Committee:

Randall Benson, MD, Medical Director, Center For Neurological Studies

Charles Bernick, MD, MPH, Associate Medical Director, Cleveland Clinic Las Vegas Lou

Ruvo Center for Brain Health

Jessica Gill, PhD, RN, FAAN, Lasker Clinical Research Scholar, National Institute of

Nursing Research

Larry Latour, PhD, Senior Scientist, National Institute of Neurological Disorders and

Stroke

Robert Driscoll, ND ’77, MD, Chief of Trauma South Shore Health Systems,

Surgical Faculty Harvard Medical School

 

 

Background and Significance

Repetitive mild traumatic brain injury (TBI), including symptomatic concussions and

subconcussive trauma, may lead to the neurodegenerative disease, chronic traumatic

encephalopathy (CTE).1-9 Exposure to these repetitive head impacts (RHI) from contact and

collision sport involvement (e.g., tackle football, boxing) has been specifically associated with

post-mortem CTE neuropathology, as well as cognitive (e.g., short-term memory problems and

executive dysfunction, problems in daily living and dementia) and neuropsychiatric (e.g.,

aggression, impulsivity, depression, apathy) decline during life. Our team at the BU CTE Center

diagnosed CTE post-mortem in a convenience sample of 177 of 202 deceased tackle football

players.7 In addition, preliminary findings from our group, of studies examining living former high

school, college, and professional tackle football players, indicated that estimated cumulative

RHI exposure, as well as the age of first exposure (AFE) to tackle football, are associated with

later life cognitive and neuropsychiatric impairment, blood and cerebrospinal fluid biomarkers of

neurodegeneration, and structural brain changes on MRI scans.10-17 CTE and other later-life

neurologic disorders from participation in tackle football is potentially a major public health

issue, given the millions of Americans who have played tackle football and the millions who

currently play.

Despite the growing media attention and public awareness of brain trauma and

neurodegenerative disease associated with American football, the actual risk for long-term

cognitive and neuropsychiatric consequences from playing football is unknown,

particularly at the college level. The existing evidence is limited by small sample sizes,

possible biases from participant recruitment methods, and a focus on former professional tackle

football players. Many millions more play or have played tackle football at the college level and

thus it is this large cohort which could possibly pose the most significant public health concern.

There is, therefore, a need for a large-scale investigation of the cognitive and neuropsychiatric

function of former college tackle football players.

In contrast to the focus these past several years on CTE and related later-life cognitive,

mood, and behavior changes in former football players, there has been very little research on

possible increased risk for other medical conditions in former football players. The limited

research that has been conducted has been on former professional (NFL) players, with very

mixed results.18-24 There is a need to study the prevalence of other medical conditions and

disorders, across all body systems. In particular, because of frequent orthopedic injuries

incurred during football, it is possible that former collegiate players may have an increased

frequency of opioid dependence initiated from later life orthopedic surgery pain management.

The ability to obtain health information and assess the cognitive and neuropsychiatric

functioning of hundreds of former college football players from a single major NCAA college

program, all between the ages of 58 and 75, provides a unique and important opportunity. Prior

to the implementation of this project, the Notre Dame Former Players Medical Research

Association had already undertaken the critically vital tasks of: (1) compiling the contact

information for, or knowledge of death of, 97% of all of the senior varsity football players from

the 17-year period of 1964-1980; (2) developing the trust and interest of their former teammates

to participate in this research; and (3) obtaining the informal support of key members of the

University of Notre Dame leadership. The establishment of a partnership with experienced

researchers from the BU CTE Center now makes possible the design and execution of a

scientifically sound and cost- and time-efficient research project, one that will likely result in

valuable findings pertinent to all of the participating former Notre Dame players, other former

college players from the same era, and all past, current, and future college football players.

 

 

Specific Aims

 

Aim 1. Determine the current overall health status of former Notre Dame football

players.

 

Aim 2. Characterize the current cognitive and neuropsychiatric functioning of former

Notre Dame football players.

 

Aim 3: Conduct annual follow-up evaluations of former players to assess future decline

in functioning and/or new disorders/diagnoses.

 

Methods

 

Sample

 

The subjects in this study comprise all of the Notre Dame senior varsity players who

were on the football teams coached by Ara Parseghian during the 11 seasons from 1964-1974

and coached by Dan Devine during the 6 seasons 1975-1980. The total number of players on

those teams is 509. In order to reduce potential ascertainment bias and other potential biases in

the sample, the goal is to gather basic health information on the entire group of 509 former

players, whether currently living or deceased. Former players from those teams have recently

created the Notre Dame Former Players Medical Research Association (a not-for-profit

organization that is independent of the University of Notre Dame). Through formal and informal

approaches, including word of mouth, the members of the Association have developed an up-todate

contact list. Prior to the initiation of this study, the Association had obtained active email

contacts for 407 (79%) of the total 509. They have determined that 89 former players (17%)

have died. There remains 72 former players (14%) for whom there is no currently known contact

information. Staff at the BU CTE Center, working under Drs. Stern and Alosco’s direction will do

extensive online and other research in an attempt to locate contact information for the missing

subjects. In addition, working with the Association, contact information will be sought for the

next-of-kin of the deceased former players in order to contact them to provide medical,

neurologic, psychiatric, substance abuse, cognitive history, and cause of death of their loved

ones.

 

Confidentiality

 

Participants (including next-of-kin) will be informed of the extensive steps taken to

assure strict confidentiality of their responses to all questions and surveys, and to cognitive test

results. These include: (1) the responses to all questions and results will be stored in a secure,

password-protected, and encrypted database at the BU School of Public Health; (2) all

responses to questions entered into the database will be de-identified (i.e., name, date of birth,

address, and other personally-identifiable information will be stored separately from the

responses to questions); (3) all study staff undergo confidentiality training and have been

trained and nationally and locally certified in the Protection of Human Subjects; (4) no

personally-identifiable information/responses will be shared with members of the Notre Dame

Former Players Medical Research Association or the University of Notre Dame; and (5) prior to

initiation of the study, the protocol (including methods of obtaining telephone- and/or onlinebased

consent) will be reviewed and approved by the BU Medical Campus Institutional Review

Board (IRB).

 

Study Design and Data Collection Steps

 

The data collection methods for this study are designed to maximize enrollment and

participation by obtaining data in a stepwise fashion as seen in the Figure 1. It is anticipated

that all or nearly all former players or next-of-kin will be willing to complete a brief (20-minute)

online questionnaire (or, if telephone interview is requested/required, the same questions asked

by trained research assistants by phone) to ascertain basic medical, neurologic, and psychiatric

history and diagnoses. Participants (or next-of kin) will then be asked to enroll into the existing

BU Longitudinal Examination to Gather Evidence of Neurodegenerative Disease (LEGEND)

Study (PI: Stern), which is one of the few prospective, longitudinal studies of contact sport

athletes. The LEGEND Study began in 2011 and involves telephone-based sport and repetitive

head impact exposure history and cognitive assessments, as well as web-based evaluations of

mood, behavior, and cognition of contact- and non-contact sport athletes across the US (further

methodological details provided below). ~1,000 former and active athletes, including ~500 male

tackle football players, are enrolled in LEGEND, leading to several important published papers

listed below. In the following section, the methods involved for each of the Specific Aims will be

described.

 

 

Figure 1 Steps of Data Collection

 

 

 

 

 

Aim 1. Determine the current overall health status of former Notre Dame football

players.

 

Health Survey – Part 1: The former Notre Dame football players (or next-of-kin for

deceased individuals) will be directly contacted through a personalized email (created and sent

through the BU BEDAC) with the sender’s name listed as the names of the three Steering

Committee co-chairs. If a former player is unable to comprehend or adequately respond to the

survey or if he has cognitive impairment resulting in a lack of decisional capacity to provide

consent, a spouse or legally authorized representative for the former player may complete the

initial survey. The email will describe the purpose of the proposed study and the associated

procedures involved, including statements that the study is being conducted through a

partnership with researchers from Boston University School of Medicine and that all responses

will be confidential. Within the email, there will be a link that interested participants can click on

and be directed to a secure, confidential, study-specific website that will provide additional

information, request informed consent, and ask the individual to respond to questions pertaining

to the following: general health status, major medical conditions and neurologic disorders;

diagnoses of mild cognitive impairment (MCI) or dementia (including Alzheimer’s disease

dementia and others); psychiatric and behavioral disorders (including substance abuse); age of

onset of each disorder; and, for deceased individuals, cause of death (completed by next-ofkin).

At the end of this initial survey, all respondents will be given information about Part 2 of the

study involving online cognitive testing, neuropsychiatric questionnaires, and a telephone

interview and asked to participate or find out more information.

 

Aim 2: Characterize the current cognitive and neuropsychiatric functioning of

former Notre Dame tackle football players, ages 58-74, as well as their estimated

repetitive head impact exposure.

 

Online Cognitive and Neuropsychiatric Testing – Part 2a: Individuals who respond to the

query at the end of the Part 1 Health Survey that they would like to participate in, or find out

more about Part 2 will be taken to a website landing page specifically designed for the Notre

Dame project. At this landing page, they will find additional information on Part 2 and, if

interested, they will be asked to provide consent to continue.

 

Four to six months after consenting, participants will receive another email containing a

link to the online cognitive testing portal. The cognitive testing will take approximately 45

minutes and will include the CogState Brief Battery (CBB), Lumos Labs NeuroCognitive

Performance Test (NCPT), and MemTrax Memory Test to highlight aspects of cognition we

believe are affected by repetitive head impacts including episodic memory, executing

functioning, attention, and psychomotor speed among others.

 

Twenty-four hours after completing the online cognitive testing, participants will receive

an email containing a link and will then be asked to completed online validated self-report

neuropsychiatric questionnaires of executive function (Behavior Rating Inventory of Executive

Function-Adult Version [BRIEF-A]), depression (Center for Epidemiologic Studies-Depression

Scale [CES-D]), daily living activities (Functional Activities Questionnaire [FAQ]), mood and

behavior related to football, (Cognitive Behavioral Mood History [CBMH]), pseudobulbar affect

(Center for Neurologic Study – Lability Scale [CNS-LS]), and apathy (Apathy Evaluation Scale

[AES]). These questionnaires will take approximately 15 minutes to complete. All of these

measures have normative data from which standardized scores will be derived, as well as cutscores

to determine the presence of clinically-meaningful levels of impairment. At the end of

these questionnaires, the participant will be notified that they will be contacted by a member of

the study staff to set up a 20-30 minute telephone-based interview.

 

Telephone Interview to Determine Estimated Repetitive Head Impact Exposure – Part

2b: After an interview time has been arranged, the study staff will contact the participant and will

interview the participant about their football and other contact sport history (e.g., seasons

played, position played, levels [youth, high school, college, semi-pro, pro) played, as well as

military history and detailed traumatic brain injury history.

 

Comparison to Normative Data and Known Health Statistics

This study does not involve the concurrent enrollment and participation of a “control

group.” Although the use of control group is often the optimal design for studies aimed at

examining risk of a health/medical issue in a specific population, in some types of research, it is

not possible to define the appropriate control (or comparison) group characteristics. For this and

other reasons (e.g., logistical complexity, lack of funding), some studies, including this proposed

study, are able to examine questions of risk and describe the current level of participants’

functioning by comparing the participants’ data (e.g., diagnoses, performance/responses on

standardized tests, death rate), to available health and mortality statistics for the larger

population (by age, sex, geographic location, etc.) and to published normative data available for

standardized tests (by age, sex, educational attainment).

 

Select Publications based on the LEGEND Study

• Seichepine DR, Stamm JM, Daneshvar DH, Riley DO, Baugh CM, Gavett BE, Tripodis

Y, Martin B, Chaisson C, McKee AC, Cantu RC, Nowinski CJ, Stern, R.A. Profile of selfreported

problems with executive functioning in college and professional football players.

J Neurotrauma. 2013;30:1299-1304. PMCID: PMC3713446

• Robbins CA, Daneshvar DH, Picano JD, Gavett BE, Baugh CM, Riley DO, Nowinski CJ,

McKee AC, Cantu RC, Stern RA. Self-reported concussion history: Impact of providing a

definition of concussion. Open Access J Sports Med. 2014;5:99-103. PMCID:

PMC4019619

• Alosco ML, Kasimis AB, Stamm JM, Chua AS, Baugh CM, Daneshvar DH, Robbins CA,

Mariani M, Hayden J, Conneely S, Au R, Torres A, McClean MD, McKee AC, Cantu RC,

Mez J, Nowinski CJ, Martin BM, Chaisson CE, Tripodis Y*, Stern RA*. Age of first

exposure to American football and long-term neuropsychiatric and cognitive outcomes.

Translational Psychiatry. 2017:7, e1236. http://rdcu.be/wqd7

• Montenigro PH, Alosco ML, Martin BM, Daneshvar DH, Mez J, Chaisson CE, Nowinski

CJ, Au R, McKee AC, Cantu RC, McClean MD, Stern RA,* Tripodis Y* Cumulative head

impact exposure predicts later-life depression, apathy, executive dysfunction, and

cognitive impairment in former high school and college football players. J Neurotrama.

2017;34(2):328-340. PMCID: PMC5220530

 

Aim 3: Conduct longitudinal, annual follow-up evaluations of former players to

assess future decline in functioning and/or new disorders/diagnoses.

Each participant will be requested to be contacted annually by study staff to undergo a

follow-up evaluation. These evaluations will be similar to those described above. These will

either be conducted through the LEGEND Study or through a new project (the “Head Impact

and Trauma Surveillance Study, HITSS) that, if funded by a grant (to be submitted in June 2019

to the National Institutes of Health), would replace the current LEGEND Study, using mostly

identical measures as LEGEND, the Brain Health Registry, and the Notre Dame Former Players

Medical Research Project.

 

Summary

Millions of individuals play or have played tackle football and may be at increased risk for

later-life dementia and related disorders. However, the direct relationship between

exposure to repetitive head impacts from tackle football and long-term cognitive and

neuropsychiatric consequences is not well characterized. Results from this project will

expand the currently limited knowledge on the long-term cognitive and neuropsychiatric

consequences of tackle football, particularly at the college level. In so doing, this study

will advance research on the diagnosis, treatment, and prevention of the long-term

neurological consequences associated with exposure to repetitive head impacts,

including CTE. In addition, this study will be one of the first to address overall later-life

health status, including diagnosed medical conditions and substance use disorders, of

former college football players.

 

Project Timeline

 

Task	Dates
Finalize design with input from Association Steering Committee	By August 29, 2018
Write, compile, and submit Institutional Review Board (IRB) proposal (including online consent forms); Reply to queries until approved	June 18 – November 8, 2018
BU School of Public Health (SPH) Biostatistics and Epidemiology Data Analytics Center (BEDAC) modifies existing online- and interviewer-entered forms and create new forms specific for this study; Develop initial email distribution; Modify online data capture methods; Harmonize data capture and management systems with LEGEND Study; Create Study-Specific Landing Page (home page)	June 18 – December 11, 2018
BU Study Staff conducts online and other searches to obtain contact information for all missing subjects (including next-of-kin for deceased)	June 18 – December 11, 2018
Finalize email distribution methods and send first batch of emails to former players	July 23 – July 28, 2018
Initiation of Health Survey – Part 1	December 12, 2018
Initiation of Part 2: Online Cognitive and Neuropsychiatric Testing and Interview Regarding Repetitive Head Impact Exposure History	April 12, 2019
Anticipated completion of Part 1 data collection	April 30, 2019
Analyze Part 1 data and prepare initial manuscript	May 1, 2019 – June 30, 2019
Share Part 1 findings and draft manuscript with Association Steering Committee	July 1, 2019
Revise Part 1 manuscript and submit to scientific journal (TBD)	September 1, 2019
Anticipated completion of Part 2 data collection	August 31, 2019
Analyze Part 2 data and prepare initial manuscript	September 1, 2019 – October 30, 2019
Share Part 2 findings and draft manuscript with Association Steering Committee	November 1, 2019
Revise Part 2 manuscript and submit to scientific journal (TBD)	December 15, 2019

 

 

 

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February 1, 2019

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