Traumatic Brain Injury and Risk for Chronic Traumatic Encephalopathy

February 28, 2020 updated by: Gary Small, MD, University of California, Los Angeles

FDDNP-PET Imaging in Persons at Risk for Chronic Traumatic Encephalopathy

This project was designed to determine brain imaging patterns using 2-(1-{6-[(2-fluorine 18-labeled fluoroethyl)methylamino]-2-naphthyl}ethylidene)malononitrile ([F-18]FDDNP) with positron emission tomography (PET) in participants with suspected Chronic Traumatic Encephalopathy (CTE), a progressive degenerative disease of the brain found in people with a history of repetitive traumatic brain injuries (TBIs), characterized by personality, behavioral, and mood disturbances, cognitive impairment, and sometimes motor symptoms. Currently, CTE can only be definitely diagnosed from neuropathological examination of the brain after autopsy. Developing tools to assist in the detection of this condition in living individuals at risk would facilitate research focusing on discovering potential prevention and treatment strategies.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

The project involved clinical and neuropsychological evaluations of participants with histories of TBI and symptoms suggestive of CTE; performing [F-18]FDDNP-PET scans on those participants; determining if patterns of [F-18]FDDNP binding in the brain differ from those of normal controls and Alzheimer's dementia (AD) (available from other studies). Prior research has shown that [F-18]FDDNP-PET produces binding patterns in the brain that indicate high concentrations of tau neurofibrillary tangles (NFTs) and amyloid plaques (Small et al, 2006).

The investigators aimed to test the following hypothesis: [F-18]FDDNP-PET scans will demonstrate cerebral patterns of binding in participants with suspected CTE that differ from cerebral patterns observed in cognitively-intact control participants and participants with AD. The [F-18]FDDNP-PET binding patterns are expected to be consistent with known plaque and tangle deposition patterns from previous neuropathology studies.

[F-18]FDDNP is a PET molecular imaging probe with high in vitro binding affinity to amyloid plaques, NFTs and fibrillar tau deposits as shown with fluorescent microscopy with non-radioactive FDDNP.

In addition to the above hypothesis, neuropathological data from autopsy follow-up (when it becomes available) will be used to determine correlations between regional plaque and tangle deposition patterns observed in neuropathological studies with imaging results from [F-18]FDDNP scans.

Background:

Emerging evidence indicates that repetitive, mild TBI may have long lasting effects following exposure during contact sports or military activities. As a result of recent military conflicts, a high proportion of U.S. veterans have returned from the wars in Iraq and Afghanistan with head injuries resulting from non-penetrating mechanisms.

The syndrome of CTE has been described in previous research performed on contact-sport athletes and military veterans (Omalu et al, 2005, 2006, 2010). In addition, studies of retired professional football players have demonstrated a high rate of dementia, AD, mild cognitive impairment, and depression (Guskiewicz et al, 2005, 2007).

Chronic Traumatic Encephalopathy consists of a characteristic neurobehavioral syndrome manifested by impaired personal and professional functioning, emotional disturbances, depression, alcohol and substance abuse, cognitive impairment, and suicidal behavior. It typically begins after a latency period of several years following single or repeated TBIs. A history of cerebral concussion may or may not be present. The neuroanatomical correlate consists of a tauopathy, the abnormal staining indicative of tau protein deposition in neuronal cell bodies and their axonal and dendritic connections. These representative changes of NFTs and neuritic threads are characteristic of CTE, and distinguish it from other forms of neurodegeneration.

Chronic Traumatic Encephalopathy has a classical distribution that differs than other forms of neurodegeneration (Barrio et al, 2015). The areas of involvement are the temporal and frontal cortices, in addition to the mesencephalon and upper pons, locus coeruleus, and substantia nigra. This distribution, along with the history of multiple exposures to mild TBI, the age distribution, and anatomical patterns further distinguishes this condition from AD and other forms of dementia.

Currently, the only method to diagnose CTE is through post-mortem brain examination, using special immuno-staining techniques for tau protein deposits in NFTs and neuritic threads. The ability to image tau protein collections in vivo in the form of NFTs would provide tremendous benefit for clinical management, treatment, and possibly prevention if a pre-morbid diagnosis could be confirmed. The implications for the sports communities, military organizations, and the general population, all of whom have potential exposure to TBI, are tremendous.

UCLA scientists have developed an in vivo method to measure NFTs, fibrillar tau deposits, and amyloid plaques in the brain. This discovery was led by Dr. Jorge Barrio (Department of Molecular and Medical Pharmacology), Dr. Gary Small (UCLA Division of Geriatric Psychiatry), and others. They sought a way to directly measure the physical evidence of AD - amyloid plaques and tau NFTs - in the living patient. A key to the discovery was the realization that the internal environments of these abnormal proteins were hydrophobic, that is, less friendly to water than to fat. Dr. Jorge Barrio synthesized a new group of compounds that thrived in these hydrophobic environments, and these molecules passed easily from the blood stream to brain tissues.

In initial autopsy studies, the UCLA group found that one of these new compounds (called FDDNP - UCLA Patent Ref. No. 1998-507-1) clearly displayed the well-defined characteristics needed to image these abnormal protein deposits. They then injected a radioactive form of the compound into the veins of living AD patients, and the PET scan accurately measured the concentration and location of the compound in the patient's brain. This allowed them to see for the first time, increased signals coming from living human brains in areas that contained dense collections of the abnormal proteins. .

The chemical marker essentially seeks out and temporarily attaches itself to the abnormal amyloid and tau deposits, thus providing a PET scan signal in the areas of the brain where the proteins are present in high concentrations. In healthy people without AD, these brain regions produce little or no signal. However, in people with the disease, the signal is so strong and accurate that it actually correlates with each individual's degree of memory impairment. The UCLA group has also found that people who are at risk for AD (mild cognitive impairment) have an [F-18]FDDNP signal pattern intermediate between cognitively-intact participants and those with AD, and that participants with a genetic risk for AD show higher [F-18]FDDNP binding (Small et al, 2006, 2009). Therefore, this technology could assist in early detection of the disease so that prevention treatments might be used prior to significant cognitive decline. It will also be useful in detecting and developing treatments for other conditions. Patients with dementias that have different treatment approaches (e.g., frontotemporal) have an an [F-18]FDDNP-PET pattern distinct from AD, as do patients with cognitive impairment associated with prion disease (Kepe et al, 2010).

Study Type

Observational

Enrollment (Actual)

24

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • Los Angeles, California, United States, 90095
        • UCLA Division of Geriatric Psychiatry, Semel Institute

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years to 88 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Military personnel and retired football players were exclusively men, whereas the comparative groups (AD, cognitively healthy controls) had a substantial proportion of women. Military personnel were significantly younger than the other three groups. Four of the seven military personnel were cognitively normal, and three had mild cognitive impairment. While the difference in education levels among participant groups did not reach statistical significance, pairwise comparisons indicated that military personnel had significantly lower education levels than both players and cognitively healthy individuals. Military personnel and players had significantly higher levels of depression and anxiety than did the comparison groups.

Description

Inclusion Criteria:

  1. Agreement to participate in study;
  2. A history of TBI resulting from, but not limited to, any of the following: contact sports, accidents, violence, or military combat;
  3. Age 18 or older;
  4. No significant cerebrovascular disease;
  5. Adequate visual and auditory acuity to allow neuropsychological testing;
  6. Screening laboratory tests without significant abnormalities that might interfere with the study.

Exclusion Criteria:

  1. Preexisting major neurological or other physical illness that could confound results (e.g., multiple sclerosis, diabetes, cancer);
  2. History of myocardial infarction within the previous year or unstable cardiac disease.
  3. Uncontrolled hypertension (systolic blood pressure > 170 or diastolic blood pressure > 100),
  4. History of significant liver disease, clinically significant pulmonary disease, diabetes, or cancer.
  5. Such current major psychiatric disorders as mania within the previous two years.
  6. Participants taking drugs that are known to affect [F-18]FDDNP-PET binding (e.g., ibuprofen, naproxen) were asked to stop taking medication one week prior to PET scan or excluded from the study.
  7. Use of any investigational drugs within the previous month, depending on drug half-life.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Cross-Sectional

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Suspected CTE
A total of 22 participants with suspected CTE were studied. Each received clinical and neuropsychological assessments, [F-18]FDDNP-PET scans, and magnetic resonance imaging (MRI) scans, or computed tomography scans if they could not tolerate MRI (to assist in PET region of interest identification).
Radiation: [F-18]FDDNP
Each participant was injected with [F-18]FDDNP, a radiolabeled molecular imaging probe, prior to receiving a PET scan.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Distribution Volume Ratio (DVR)
Time Frame: Baseline
The outcome measure is a ratio of the volume (in milliliters) of 2-(1-{6-[(2-fluorine 18-labeled fluoroethyl)methylamino]-2-naphthyl}ethylidene)malononitrile ([F-18]FDDNP) bound within the region of interest (ROI) divided by the amount of [F-18]FDDNP in the cerebellum (reference region). Higher ratios are indicative of higher levels of tau and amyloid proteins within the ROI. The unit of measure is called the Distribution Volume Ratio (DVR).
Baseline

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of California, Los Angeles

Investigators

  • Principal Investigator: Gary W Small, M.D., UCLA Division of Geriatric Psychiatry

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 1, 2013

Primary Completion (Actual)

October 1, 2018

Study Completion (Actual)

December 1, 2018

Study Registration Dates

First Submitted

November 5, 2013

First Submitted That Met QC Criteria

December 2, 2013

First Posted (Estimate)

December 6, 2013

Study Record Updates

Last Update Posted (Actual)

March 3, 2020

Last Update Submitted That Met QC Criteria

February 28, 2020

Last Verified

February 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 11-001077
  • IND 74944 (Other Identifier: FDA)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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