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Traumatic Brain Injury and Risk for Chronic Traumatic Encephalopathy (TBI and CTE)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02003183
Recruitment Status : Active, not recruiting
First Posted : December 6, 2013
Last Update Posted : October 16, 2018
Information provided by (Responsible Party):
Gary Small, MD, University of California, Los Angeles

Brief Summary:

The project is designed to assess early diagnosis of Chronic Traumatic Encephalopathy (CTE), a neurobehavioral syndrome manifested by failed relationships, marriages, and businesses, emotional disturbances, depression, alcohol and substance abuse, and suicide attempts and completions. CTE typically begins after a latency period of several years following single or repeated Traumatic Brain Injuries (TBIs). A history of cerebral concussion may or may not be present.

This study builds upon prior work at UCLA using Positron Emission Tomography (PET) to identify normal and abnormal functional patterns in the brain by studying persons with a history of TBI including but not limited to: amateur and professional athletes, active and veteran members of the armed forces, as well as victims of motor vehicle and work accidents, and physical battery/domestic violence.

This project aims to expand these findings to the population at large. Identification of the syndrome is critical for identifying potential individuals who are most likely to benefit from potential prevention and treatment.

Condition or disease Intervention/treatment Phase
Traumatic Brain Injury Chronic Traumatic Encephalopathy Concussions Mild Cognitive Impairment Radiation: [F-18]FDDNP Phase 2

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Detailed Description:

Specific Aims:

The proposed project will focus on application of small molecule radiolabeled probes of tau neurofibrillary tangles (NFTs) for in vivo positron emission tomography (PET) imaging of brain pathology for early detection and treatment monitoring of Chronic Traumatic Encephalopathy (CTE) and related neurodegenerative diseases (dementias and cognitive impairment).

Investigators plan to test the following hypothesis: PET imaging with small molecule probes, in the form of novel fluorescent dyes with radioactive labels, will demonstrate distinct cerebral patterns of binding in subjects with CTE. These cerebral patterns will differentiate from those of age-matched persons who are cognitively intact or from the patients with other neurodegenerative diseases.

The binding patterns will match the disease specific pattern of brain pathology characteristic for CTE (or other dementias, when studied). CTE distinguishes itself from other dementias by its clear tauopathy: NFTs and neuritic threads. In addition, brains of CTE subjects show white matter changes and inflammation.

In order to assess in vivo deposition of CTE's tauopathy, investigators propose to use PET imaging with [F-18]FDDNP, a molecular imaging probe for PET, with high in vitro binding affinity to NFTs and of the fibrillar tau deposits as shown with fluorescent microscopy with non-radioactive FDDNP. The analysis of [F-18]FDDNP will allow investigators to evaluate the specificity and sensitivity of this imaging probe for detection of the brain pathology and utilization of these methods for detection of early deposition and for monitoring of any therapeutic intervention aimed at stopping or reducing the deposition of neuropathologic aggregates.

Simple blood-based biomarkers that correlate biochemical changes to clinical or cognitive status, when used in conjunction with genetic risk status, may increase the power of predicting who will decline in an asymptomatic population. An additional aspect of this protocol is to obtain blood based biomarker information to identify differences in markers of CTE sufferers. Better characterizing the relationship between various biochemical markers and disease status may allow us to improve our understanding of CTE causes, enhance our ability to diagnose early, and may lead to more effective treatments in the future. Researchers propose investigating several blood-based biomarkers related to inflammation, (Interleukin (IL)-1, I-309, IL-6, IL-13, and superoxide dismutase 3; SOD3) in diseased (clinical diagnosis of AD) and healthy APOE e3 and APOE e4 carrying individuals to better characterize inflammation levels in these genetic groups.

In addition to the above hypotheses, neuropathological data from autopsy follow-up will be used to determine correlations between regional plaque and tangle deposition patterns and PET signals. Investigators will create PET cortical surface maps for [F-18]FDDNP-PET between subjects with Traumatic Brain Injury and controls compared with region of interest analysis in transaxial PET images. MRI scans will be available for diffusion tensor imaging (DTI), and investigators will use these DTI measures to confirm our anticipated findings of greater white matter integrity in controls compared with AD patients.


Emerging evidence indicates that repetitive, mild traumatic brain injury (MTBI) may have long lasting effects following exposure during contact sports or military activities. As a result of the recent military conflicts, 95% of U.S. veterans have returned from the war returning from the war in Iraq and Afghanistan with head injuries resulting from non-penetrating mechanisms.

The syndrome of Chronic Traumatic Encephalopathy (CTE) has been established by WVU researchers in 25 contact-sport athletes, including one military veteran previously diagnosed as having Post Traumatic Stress Disorder. CTE was first diagnosed in 2005 by the neuropathologist Bennet Omalu, M.D. (1-3). In addition, studies of retired NFL players have found a high incidence of dementia, Alzheimer's disease, mild cognitive impairment, and depression in these patients. The only correlative risk factor was the presence of three or more significant concussions or MTBI's during their NFL playing career (4,5).

Chronic Traumatic Encephalopathy consists of a characteristic neurobehavioral syndrome manifested by failed relationships, marriages, and businesses, emotional disturbances, depression, alcohol and substance abuse, and suicide attempts and completions. It typically begins after a latency period of several years following single or repeated Traumatic Brain Injuries (TBIs). A history of cerebral concussion may or may not be present. The clinical syndrome usually terminates in suicide (6-8). 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 neurofibrillary tangles (NFTs) and neuritic threads (NTs) are characteristic of CTE, and distinguish it from other forms of dementia. In addition, white matter changes and inflammation are also seen in these brain specimens (8).

Chronic Traumatic Encephalopathy has a classical distribution that differs than other forms of dementia, and sub-typing based on location and distribution is reflected in the recent Omalu-Bailes classification (8). The areas of involvement are the temporal and frontal cortices, in addition to the mesencephalon and upper pons, locus cereuleus, and substantia nigra. This distribution, along with the history of multiple exposures to MTBI, the age distribution, and anatomical patterns further distinguishes this condition from Alzheimer's disease and other forms of dementia. In addition, 70% of athletes diagnosed postmortem with CTE are positive for apolipoprotein A3 (8).

Currently, the only method to diagnose CTE is through post-mortem brain examination, utilizing special immuno-staining techniques for tau protein deposits in NFTs and NTs. 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 MTBI, are tremendous.

UCLA scientists have developed the only currently available in vivo method to measure NFTs and of the fibrillar tau deposits in the brain. This discovery was led by Dr. Jorge Barrio (Molecular and Medical Pharmacology), Dr. Gary Small (UCLA Center on Aging, Aging and Memory Research Center at the Semel Institute at UCLA), and others, working in the UCLA PET scan program. They sought a way to directly measure the physical evidence of Alzheimer's disease - the abnormal amyloid brain protein deposits including 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 amyloid proteins characteristic of the disease. They then injected a radioactive form of the compound into the veins of living Alzheimer's patients, and the PET scan accurately measured the concentration 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, thus providing a clear PET scan signal in the areas of the brain where Alzheimer's strikes. In healthy people without Alzheimer's, 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 Alzheimer's disease (mild cognitive impairment) have an amyloid-PET pattern intermediate between normal people and patients with Alzheimer's and that [F-18]FDDNP binding is influenced by APOE-4 status (9,10). Therefore, this technology will likely 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 Alzheimer's, as do patients with cognitive impairment associated with prion disease(11).

Potential participants will be screened via telephone by a staff member to determine eligibility. Subjects who meet eligibility criteria will be enrolled. Oral consent will be required to perform the telephone screen.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: FDDNP-PET Imaging in Persons at Risk for Chronic Traumatic Encephalopathy
Study Start Date : March 2013
Actual Primary Completion Date : October 2018
Estimated Study Completion Date : October 2018

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: [F-18]FDDNP Radiation: [F-18]FDDNP
[F-18]FDDNP is a molecular imaging probe for PET, with high in vitro binding affinity to NFTs and of the fibrillar tau deposits as shown with fluorescent microscopy with non-radioactive FDDNP.

Primary Outcome Measures :
  1. FDDNP PET will detect tau deposits in the brain of living subjects at risk for CTE [ Time Frame: Baseline ]
    FDDNP signals will be higher in those affected by CTE compared with controls in all subcortical regions and the amygdala areas that produce tau deposits following trauma.

Secondary Outcome Measures :
  1. Correlation of genetic risk factors and FDDNP-PET measurements [ Time Frame: Baseline ]
    FDDNP-PET measures will vary according to genotypes found to influence age at dementia onset (e.g., apolipoprotein E [APOE]).

Other Outcome Measures:
  1. Cognitive Impairment will be observed in subjects at risk of CTE [ Time Frame: Baseline ]
    Affected subjects will show greater depressive symptoms than controls as well as cognitive impairment.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   30 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

Inclusion Criteria:

  1. Agreement to participate in study
  2. A history of Traumatic Brain Injury resulting from, but not limited to, any of the following: sports, accidents, violence, and military combat.
  3. Age 18 or older
  4. No significant cerebrovascular disease - modified Ischemic Score of ≤ 8 (Rosen et al, 1980)
  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 neurologic 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 BP > 170 or diastolic BP > 100),
  4. History of significant liver disease, clinically significant pulmonary disease, diabetes, or cancer.
  5. Such current major psychiatric disorders as mania, according to DSM-IV TR criteria, within the previous two years (APA, 2000).
  6. Subjects taking drugs that are known to affect FDDNP-PET binding (e.g., ibuprofen, naproxen) will be 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 or longer, depending on drug half-life will exclude subjects.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02003183

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United States, California
UCLA Longevity Center
Los Angeles, California, United States, 90095
Sponsors and Collaborators
University of California, Los Angeles
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Principal Investigator: Gary W Small, M.D. UCLA Longevity Center

Additional Information:
Publications of Results:
Other Publications:

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Responsible Party: Gary Small, MD, Principal Investigator, University of California, Los Angeles Identifier: NCT02003183     History of Changes
Other Study ID Numbers: 11-001077
IND 74944
First Posted: December 6, 2013    Key Record Dates
Last Update Posted: October 16, 2018
Last Verified: October 2018
Keywords provided by Gary Small, MD, University of California, Los Angeles:
Cognitive Impairment
Brain Imaging
Additional relevant MeSH terms:
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Brain Injuries
Brain Injuries, Traumatic
Brain Diseases
Chronic Traumatic Encephalopathy
Cognitive Dysfunction
Wounds and Injuries
Central Nervous System Diseases
Nervous System Diseases
Craniocerebral Trauma
Trauma, Nervous System
Cognition Disorders
Neurocognitive Disorders
Mental Disorders
Brain Injury, Chronic
Neurodegenerative Diseases