The DIAGNOSE-CTE Research Project (DIAGNOSE-CTE)

Diagnostics, Imaging And Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy (DIAGNOSE CTE) Research Project

This is a study to develop methods of diagnosing chronic traumatic encephalopathy (CTE) during life, as well as to examine possible risk factors for this neurodegenerative disease. One component of this study is the use of an investigational PET scan radio tracer to detect abnormal tau protein in the brain.

Study Overview

• Status: Completed
• Conditions: Chronic Traumatic Encephalopathy

Detailed Description

Chronic Traumatic Encephalopathy (CTE) is a neurodegenerative disease characterized by a distinct deposition of phosphorylated tau (p-tau) in neurons and astrocytes in a pattern that is unique from other tauopathies, including Alzheimer's disease (AD). Although the neuropathological features of CTE have become further clarified in recent years, the clinical presentation of CTE is still not well characterized. Diagnostic criteria have only recently been published and lack validation.

Neuroimaging and fluid biomarkers developed for the diagnosis of other neurodegenerative diseases have only been used in preliminary studies of individuals at high risk for CTE, namely athletes with histories of significant exposure to repetitive head impacts (RHI), such as former football players and boxers. There is thus an urgent need to develop accurate methods for detecting and diagnosing CTE during life so that effective interventions for prevention and treatment can be developed. Moreover, though a history of RHI is a necessary risk factor for CTE, it alone is not sufficient. There is a need to understand what specific aspects of RHI exposure places an individual at increased risk for CTE and to examine potential genetic polymorphisms that modify that risk.

To address these needs, the investigators are conducting a multidisciplinary, multicenter, longitudinal study of former NFL and varsity college football players (with and without symptoms), and a control group of asymptomatic same-age men without any history of RHI exposure, traumatic brain injury or military service. Subjects will be seen at 1 of 4 participating study sites in Boston; Las Vegas, ; New York; and Scottsdale/Phoenix . Subjects will undergo a baseline evaluation and a 3 year follow-up evaluation (currently former college players will not complete the follow-up evaluation). Each evaluation will be take place over a 3 day period and consist of the following procedures/tests: neurocognitive testing, determination of functional independence, neuropsychiatric examination (with measures of mood and behavior), neurological assessment (motor, headache, postural stability), neuroimaging (including structural, diffusion, functional, biochemical, and molecular imaging), lumbar punctures (for Cerebrospinal Fluid (CSF) biomarkers), blood draws (for blood biomarkers and DNA), and saliva samples (for biomarkers).

• Study Type: Observational
• Enrollment (Actual): 240

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years to 74 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Former National Football League Players, Former Varsity Level College Football Players, Healthy Controls

Description

Inclusion Criteria:

Former NFL Players:

• English as primary language
• No MRI or Lumbar Puncture (LP) contraindications
• Have played ≥12 years of organized football (including =>3 in college and =>3 seasons in the NFL)
• Must have played one of following positions offensive lineman, defensive lineman, linebacker, tight end, wide receiver, running back, or defensive back.
• Agree to provide name and contact information of a study partner who will complete questionnaires regarding subject's mood, behavior, thinking and cognitive function should the subject enroll in the study.

Former Collegiate Football Players

• English as primary language
• No MRI or Lumbar Puncture (LP) contraindications
• Must have played =>6 years of organized football (with => 3 years at the college level, but no organized football or other contact sport following college.)
• Must have played one of following positions offensive lineman, defensive lineman, linebacker, tight end, wide receiver, running back, or defensive back.
• No military service
• Agree to provide name and contact information of a study partner who will complete questionnaires regarding subject's mood, behavior, thinking and cognitive function should the subject enroll in the study.

Control Group

• English as primary language
• No MRI or Lumbar Puncture (LP) contraindications
• No history of organized contact sports or known traumatic brain injury (TBI) and/or moderate/severe concussions
• No history of participation in any of the following organized sports at any level: football, hockey, rugby, soccer, lacrosse, wrestling, boxing, gymnastics, martial arts, and kickboxing.
• No military service.
• Must have BMI >=24
• Must have at least 2 years post-secondary education at a 4-year accredited college or university, or have an associate's degree if they did not attend a 4-year accredited college or university
• Must have never been diagnosed with, or treated for, any of the following: depression, manic-depressive or bipolar disorder, anxiety, or other psychiatric or mental health problems
• Agree to provide name and contact information of a study partner who will complete questionnaires regarding subject's mood, behavior, thinking and cognitive function should the subject enroll in the study.
• Must be asymptomatic when screened by telephone.

Former NFL and Varsity Collegiate Football Players Exclusion Criteria:

• If they do not meet inclusion criteria
• If they have a history of clinical stroke confirmed on neuroimaging
• If they have vision or hearing impairment significant enough to compromise neuropsychological testing
• If they have been hospitalized or treated in an emergency room following a severe injury to their head since they stopped playing football
• If they are unable to undergo MRI/PET Scan
• If they have a spinal fusion at L3-4 and/or L4-5
• If they are unable to travel to one of 4 study sites to participate
• If they are an insulin dependent diabetic
• If they cannot provide the name and contact information of an eligible study partner
• If they are taking blood thinners that would make LP unsafe
• If they have a type of abnormal heart rhythm called Torsades de pointes AKA TdP
• If they have an abnormal heart rhythm disorder called QT Prolongation or take certain medications known to cause QT Prolongation
• If they do not agree to all study tests and procedures
• If they are unable to consent to study procedures

Control Group Exclusion:

• If they do not meet inclusion criteria
• If they have vision or hearing impairment significant enough to compromise neuropsychological testing
• If they are unable to undergo MRI/PET Scan
• If they have a spinal fusion at L3-4 and/or L4-5
• If they are an insulin dependent diabetic
• If they are unable to travel to one of 4 study sites to participate
• If they cannot provide the name and contact information of an eligible study partner
• If they report any cognitive concerns or dementia during screening process
• If they have a type of abnormal heart rhythm called Torsades de pointes AKA TdP
• If they have an abnormal heart rhythm disorder called QT Prolongation or take certain medications known to cause QT Prolongation
• If they are unable to consent to study procedures

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
Former NFL Players; 120 former National Football League players with and without reported cognitive, mood and behavior symptoms will be enrolled in this study.
Former College Football Players; 60 former college football players with and without reported cognitive, mood and behavior symptoms will be enrolled in this study.
Control Group; 60 asymptomatic same-age men without any history of participation in contact sports, military service, or traumatic brain injury will be enrolled in this study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neuroimaging Positron Emission Tomography for Amyloid Biomarker	Subjects will undergo a Florbetapir Positron Emission Tomography (PET) scan. The Outcome Measurement for the Florbetapir PET Scan will be "elevated" or "not elevated"	One-Time
Fluid Biomarkers	The following Biospecimens will be collected from subjects: Saliva, blood and cerebral spinal fluid (CSF). CSF will be collected by a lumbar puncture (spinal tap) Fluid biomarkers will be analyzed for the in vivo detection of CTE.	3 Years
Neuropsychiatric and Neurocognitive Tests	Composite scores (presented as z scores) based on factor analytic methodology in the following domains: Mood; Behavior Regulation; Attention, Information Processing and Psychomotor Speed; Executive Functioning; Verbal Memory; Visual Memory; Visual-Spatial Ability; Language	3 years
Neurological Evaluation	Subjects will undergo The Movement Disorder Society's Unified Parkinson's Disorders Rating Scale (MDS-UPDRS) Neurological Evaluation by a physician. This evaluation will be analyzed to characterize the clinical presentation of CTE.	3 years
Magnetic Resonance Imagining Biomarkers	Subjects will undergo Diffuser Tension Imaging (dti) and Functional MRI scans, to assess structural brain volumetrics, fractional anisotropy, radial diffusivity, and changes in brain activity associated with blood flow.	3 years
Neuroimaging Positron Emission Tomography for Tau Biomarker	Subjects will undergo an Investigational drug: AV1451 Positron Emission Tomography (PET) scan. The Outcome Measurement for AV1451 PET scan will be Standardized Uptake Value Ratio (SUVR) of Tau.	3 years
Magnetic Resonance Spectroscopy Biomarkers	Subject will also undergo Magnetic Resonance Spectroscopy (MRS) to measure glutamate, glutamine and myoinosotol.	3 years

Collaborators and Investigators

• Sponsor: Boston University
• Collaborators: Mayo Clinic; National Institute of Neurological Disorders and Stroke (NINDS); NYU Langone Health; The Cleveland Clinic; Brigham and Women's Hospital; Banner Health
• Investigators: Principal Investigator: Robert A Stern, PhD, Boston University

Publications and helpful links

General Publications

• Alosco ML, Mariani ML, Adler CH, Balcer LJ, Bernick C, Au R, Banks SJ, Barr WB, Bouix S, Cantu RC, Coleman MJ, Dodick DW, Farrer LA, Geda YE, Katz DI, Koerte IK, Kowall NW, Lin AP, Marcus DS, Marek KL, McClean MD, McKee AC, Mez J, Palmisano JN, Peskind ER, Tripodis Y, Turner RW 2nd, Wethe JV, Cummings JL, Reiman EM, Shenton ME, Stern RA; DIAGNOSE CTE Research Project Investigators. Developing methods to detect and diagnose chronic traumatic encephalopathy during life: rationale, design, and methodology for the DIAGNOSE CTE Research Project. Alzheimers Res Ther. 2021 Aug 12;13(1):136. doi: 10.1186/s13195-021-00872-x.

Helpful Links

• Study website

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2016
• Primary Completion (Actual): October 31, 2023
• Study Completion (Actual): November 15, 2023

Study Registration Dates

• First Submitted: May 20, 2016
• First Submitted That Met QC Criteria: June 13, 2016
• First Posted (Estimated): June 14, 2016

Study Record Updates

• Last Update Posted (Estimated): December 5, 2023
• Last Update Submitted That Met QC Criteria: December 1, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Disease Attributes; Brain Damage, Chronic; Neurodegenerative Diseases; Craniocerebral Trauma; Trauma, Nervous System; Brain Injuries; Chronic Disease; Brain Injury, Chronic; Brain Injuries, Traumatic; Brain Diseases; Chronic Traumatic Encephalopathy
• Other Study ID Numbers: H-34799; U01NS093334 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified data will be shared with FITBIR and other data sharing portals

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No