Background
Neuropathology of CTE
Risk factors for CTE
Clinical presentation of CTE and traumatic encephalopathy syndrome
The DIAGNOSE CTE Research Project
Aim 1: To collect and analyze neuroimaging and fluid biomarkers for the in vivo detection of CTE. | |
Aim 2: To characterize the clinical presentation of CTE. | |
Aim 3: To examine the progression of CTE in a longitudinal study. | |
Aim 4: To refine diagnostic criteria for the clinical diagnosis of CTE. | |
Aim 5: To investigate genetic and head impact exposure risk factors for CTE. | |
Aim 6: To share project data with researchers across the country and abroad. |
Methods
Infrastructure overview
Sample selection
Inclusion criteria | Exclusion criteria | |
---|---|---|
All participants (N = 240) | Male; age 45–74; no contraindications for MRI, LP, or PET procedures; English as primary language; agree to all procedures; willingness to have and availability of a study partner (i.e., informant who knows the participant well, speaks or visits with participant at least weekly for a minimum of 6 months, is > 18 years of age, has English as primary language) who agrees to participate in a telephone interview and respond to a series of online questionnaires. | History of clinical stroke or significant neurologic condition; vision or hearing impairment severe enough to compromise neuropsychological testing; impaired decisional capacity to provide informed consent to participate in study; currently clinically significant infectious disease, endocrine or metabolic disease, pulmonary, kidney or liver impairment, or cancer; body weight > 400 pounds |
Unexposed group (UE) (N = 60) | No history of participation in organized contact/collision sportsa or military combat service or training; asymptomatic, based on telephone screening questionsb (asked of both participant and informant) regarding current mood, behavior, or cognitive symptoms, as well as functional dependence; have at least 2 years of post-secondary education at a 4-year accredited college/university, or have an associate’s degree | History of TBI or concussion; history of formal diagnosis or treatment of psychiatric illness or cognitive impairment; body mass index (BMI) < 24 |
Former college football player group (COL) (N = 60) | Played > 6 years of organized American football, with > 3 years at the college varsity level; played one of the following positionsc while in college: offensive lineman, defensive lineman, linebacker, offensive back or receiver, or defensive back (individuals whose primary position was kicker or quarterback were not included); no organized football or other contact/collision sport following college | |
Former professional football player group (PRO) (N = 120) | Played ≥ 12 years of organized football, including > 3 in college and > 3 seasons in the NFL; played one of the following positionsc while in the NFL: offensive lineman, defensive lineman, linebacker, offensive back or receiver, or defensive back (individuals whose primary position was kicker or quarterback were not included) |
Sample size determination and power
Recruitment and retention
Study procedures
Data collection
Clinical evaluations
Domain | Test/Instrument | Baseline | Follow-up |
---|---|---|---|
Neurologic exam | Semi-structured clinical examination of cranial nerves, sensory functions, muscle strength, fasciculations, and reflexes | I | – |
Motor | International Parkinson and Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) [101] | I | V |
Timed Up and Go (TUG) [102] | I | – | |
Effort (symptom validity) | I | V | |
Estimated premorbid intelligence | Wide Range Achievement Test-Fourth Edition (WRAT-4) Word Reading [] | I | – |
Cognitive screening | I | T,V | |
Attention, visual scanning, and psychomotor speed | Symbol Digit Modalities Test [108] | I | V |
Trail Making Test Part A [109] | I | – | |
Unified Data Set (UDS) Number Span Test [110] | I | T | |
Executive function | Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) Global Executive Composite (GEC; Participant and Informant) [111] | R | R |
BRIEF-A Metacognition Index (MI; Participant and Informant) [111] | R | R | |
Phonemic Fluency - Controlled Oral Word Association Test (COWAT) [112] | I | T | |
Golden Stroop Color and Word Interference [98] | I | – | |
I | – | ||
Trail Making Test Part B [109] | I | – | |
NAB Categories [99] | – | V | |
– | C | ||
– | C | ||
– | C | ||
Learning and memory | Brief Visuospatial Memory Test – Revised (BVMT-R) [104] | I | V |
UDS Craft Story [110] | I | T | |
NAB List Learning [99] | I | T | |
– | C | ||
– | C | ||
Language | I | T | |
– | T | ||
UDS Multilingual Naming Test (MINT) [110] | I | V | |
Visuospatial ability | Judgment of Line Orientation (JOLO) [117] | I | V |
BVMT-R Copy [104] | I | V | |
Emotional facial perception | – | C | |
Dementia severity | Functional Activities Questionnaire (FAQ; Participant and Informant) [118] | R | R |
Quick Dementia Rating System (QDRS; Participant and Informant) [119] | R | R | |
Sleep | Mayo Sleep Questionnaire (MSQ; Participant and Informant) [120] | R | R |
Epworth Sleepiness Scale [121] | R | R | |
Olfactory | Brief Smell Identification Test (B-SIT) [122] | I | – |
Pain | Headache Impact Test (HIT-6) [123] | R | R |
P | P | ||
Substance use | Alcohol Use Disorders Identification Test: Interview Version (AUDIT) [126] | I | T |
Modified National Institute on Drug Abuse (NIDA) Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) version 2.0 [127] | I | T | |
Health status | EQ-5D-5L Health Questionnaire [128] | P | P |
National Health and Nutrition Examination Survey (NHANES) Physical Activity and Physical Fitness Questionnaire (PAQ) [129] | I | T | |
NHANES Weight History Questionnaire [130] | I | T |
Domain | Instrument |
---|---|
Affective lability | Center for Neurologic Study – Lability Scale (CNS-LS) [131] |
Behavior | Barratt Impulsivity Scale-11 (BIS-11) [132] |
BRIEF-A Behavioral Regulation Index (BRI; Participant and Informant) [111] | |
Brown-Goodwin Lifetime History of Aggression (BGLHA) [133] | |
Buss-Durkee Hostility Inventory (BDHI) [134] | |
Mild Behavioral Impairment – Checklist (MBI-C; Participant and Informant) [135]* | |
Neuropsychiatric Inventory – Questionnaire (NPI-Q; Informant) [136] | |
State-Trait Anger Expression Inventory-II (STAXI-II) [137] | |
Depression, anxiety, apathy, other | Apathy Evaluation Scale (AES) [138] |
Beck Anxiety Inventory (BAI) [139] | |
Beck Depression Inventory-II (BDI-II) [140] | |
Beck Hopelessness Scale (BHS) [141] | |
PTSD Checklist – Civilian Version (PCL-C) [142] | |
Sheehan-Suicidality Tracking Scale (S-STS) [143] | |
University of California, Los Angeles Loneliness Scale (UCLA) [144] |
Neuroimaging
Fluid biomarkers
Head impact exposure assessment and modeling
Genetics
Multidisciplinary Diagnostic Consensus Conferences (MDCC)
Modified remote follow-up evaluations
Management and sharing of data and biospecimens
Results
Participants
Former NFL players (PRO) | Former college football players (COL) | Unexposed (UE) | p valuea | |
---|---|---|---|---|
Total N | 120 | 60 | 60 | – |
Age, mean (SD) years | 59.1 (7.8) | 53.5 (7.7) | 59.3(8.3) | < 0.01b |
Age by decade, n (%) years | ||||
45–54 | 42 (35.0) | 44 (73.3) | 23 (38.3) | < 0.01 |
55–64 | 46 (38.3) | 9 (15.0) | 15 (25.0) | |
65–75 | 32 (26.7) | 7 (11.7) | 22 (36.7) | |
Body mass index, mean (SD) kg/m2 | 32.0 (4.5) | 33.8 (4.8) | 30.8 (4.5) | < 0.01c |
Years of education, mean (SD) | 16.6 (1.1) | 17.1 (1.0) | 17.3 (3.4) | 0.38 |
Level of education, n (%) | ||||
Some college, no degree | 15 (12.5) | 5 (8.3) | 7 (11.7) | < 0.01 |
Associate degree | 2 (1.7) | 1 (1.7) | 8 (13.3) | |
Bachelor’s degree | 82 (68.3) | 35 (58.3) | 23 (38.3) | |
Master’s degree | 16 (13.3) | 17(28.3) | 12 (20.0) | |
Doctoral degree | 5 (4.2) | 2 (3.4) | 10 (16.7) | |
Racial Identity, n (%) | ||||
American Indian or Alaska Native | 1 (0.8) | 0 (0.0) | 0 (0.0) | 0.05 |
Black or African American | 51 (42.5) | 10 (16.7) | 24 (40.0) | |
Native Hawaiian or other Pacific Islander | 0 (0.0) | 0 (0.0) | 1 (1.7) | |
White | 66 (55.0) | 48 (80.0) | 35 (58.3) | |
Multiracial | 1 (0.8) | 1 (1.7) | 0 (0.0) | |
Not reported | 1 (0.8) | 1 (1.7) | 0 (0.0) | |
Ethnicity, n (%) | ||||
Hispanic or Latino | 3 (2.5) | 0 (0.0) | 0 (0.0) | 0.28 |
Not Hispanic or Latino | 117 (97.5) | 60 (100.0) | 59 (98.3) | |
Unknown/not reported | 0 (0.0) | 0 (0.0) | 1 (1.7) | |
Marital status, n (%) | ||||
Never married | 5 (4.2) | 3 (5.0) | 15 (25.0) | < 0.01 |
Married or domestic partnership | 88 (73.3) | 43 (70.0) | 31 (51.6) | |
Divorced or separated | 23 (19.2) | 14 (23.3) | 13 (21.7) | |
Widowed | 1 (0.8) | 1 (1.7) | 0 (0.0) | |
Other | 3 (2.5) | 0 (0.0) | 1 (1.7) | |
Employment status, n (%) | ||||
Working full-time | 57 (47.5) | 40 (66.7) | 27 (45.0) | < .01 |
Working part-time | 10 (8.3) | 0 (0.0) | 11 (18.3) | |
Unemployed | 1 (0.8) | 7 (11.7) | 1 (1.7) | |
Retired | 38 (31.7) | 9 (15.0) | 21 (35.0) | |
Disabled | 13 (10.8) | 2 (3.3) | 0 (0.0) | |
Other/refused | 1 (0.8) | 2 (3.3) | 0 (0.0) | |
Level of father’s education, n (%) | ||||
Less than high school | 24 (20.0) | 3 (5.0) | 8 (13.3) | 0.01 |
High school diploma or graduate equivalent degree (GED) | 43 (35.8) | 15 (25.0) | 18 (30.0) | |
Some college or associate degree | 10 (8.3) | 11 (18.3) | 6 (10.0) | |
Bachelor’s degree | 15 (12.5) | 19 (31.7) | 12 (20.0) | |
Master’s degree | 9 (7.5) | 6 (10.0) | 10 (16.7) | |
Doctoral degree | 7 (5.8) | 4 (6.7) | 3 (5.0) | |
Unknown | 12 (10.0) | 2 (3.3) | 3 (5.0) | |
Level of mother’s education, n (%) | ||||
Less than high school | 19 (15.8) | 4 (6.7) | 5 (8.3) | 0.04 |
High school diploma or GED | 52 (43.3) | 21 (35.0) | 22 (36.7) | |
Some college or associate degree | 16 (13.3) | 11 (18.3) | 11 (18.3) | |
Bachelor’s degree | 18 (15.0) | 17 (28.3) | 10 (16.7) | |
Master’s degree | 6 (5.0) | 6 (10.0) | 8 (13.3) | |
Doctoral degree | 1 (0.8) | 1 (1.7) | 3 (5.0) | |
Unknown | 8 (6.7) | 0 (0.0) | 1 (1.7) | |
History of learning disability or ADHD, n (%) | 9 (7.5) | 10 (16.7) | 1 (1.7) | 0.02 |
Site evaluated, n (%) | ||||
Boston | 26 (21.7) | 18 (30.0) | 20 (33.3) | 0.58 |
Las Vegas | 33 (27.5) | 13 (21.7) | 11 (18.3) | |
New York | 28 (23.3) | 15 (25.0) | 16 (26.7) | |
Scottsdale/Phoenix | 33 (27.5) | 14 (23.3) | 13 (21.7) | |
Primary position at highest level of football, n (%) | ||||
Offensive lineman | 22 (18.3) | 22 (36.7) | – | 0.09 |
Defensive lineman | 14 (11.7) | 5 (8.3) | ||
Offensive back or receiver | 36 (30.0) | 14 (23.3) | ||
Linebacker | 21 (17.5) | 7 (11.7) | ||
Defensive back | 23 (19.2) | 12 (20.0) | ||
Special teams | 4 (3.3) | 0 (0.0) | ||
Total years of football, mean (SD) | 18.0 (3.3) | 11.5 (2.5) | – | < 0.01 |
Total fall seasons of college football, mean (SD) | 4.1 (0.5) | 3.9 (0.6) | – | 0.11 |
Total years of NFL participation, mean (SD) | 7.4 (2.7) | – | – | – |
Age of first exposure to football, mean (SD) | 11.5 (2.8) | 10.2 (2.6) | – | < 0.01 |
Neuroimaging data available, n (%) | ||||
Magnetic resonance imaging | 114 (95.0) | 55 (91.7) | 56 (93.3) | – |
Tau PET – Flortaucipir | 112 (93.3) | 58 (96.7) | 58 (96.7) | |
Amyloid PET – Florbetapir | 119 (99.2) | 60 (100.0) | 58 (96.7) | |
Biofluids collected, n (%) | ||||
Cerebrospinal fluid | 102 (85.0) | 40 (66.7) | 46 (76.7) | – |
Blood (plasma, serum, whole blood) | 118 (98.3) | 58 (96.7) | 58 (96.7) | |
Saliva | 120 (100.0) | 60 (100.0) | 58 (96.7) | |
MoCA total raw score, mean (SD) | 24.3 (3.5) | 25.4 (3.2) | 26.5 (2.3) | < 0.01d |
Functional Activities Questionnaire – Informant Total, mean (SD) | 3.9 (5.5) | 3.2 (4.9) | 0.4 (2.4) | < 0.01e |
ApoE genotype – n (%) ε4 carriersf | 33 (28.7) | 20 (33.9) | 11 (19.6) | 0.22 |