Traumatic Brain Injury and Risk for Chronic Traumatic Encephalopathy

• ClinicalTrials.gov Identifier: NCT02003183
• Recruitment Status: Completed
• First Posted: December 6, 2013
• Results First Posted: November 27, 2019
• Last Update Posted: March 3, 2020
• Sponsor: University of California, Los Angeles
• Information provided by (Responsible Party): Gary Small, MD, University of California, Los Angeles

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment
CTE; TBI (Traumatic Brain Injury)	Radiation: [F-18]FDDNP

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 Design

• Study Type: Observational
• Actual Enrollment: 24 participants
• Observational Model: Cohort
• Time Perspective: Cross-Sectional
• Official Title: FDDNP-PET Imaging in Persons at Risk for Chronic Traumatic Encephalopathy
• Actual Study Start Date: March 2013
• Actual Primary Completion Date: October 2018
• Actual Study Completion Date: December 2018

Groups and Cohorts

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.

Outcome Measures

Primary Outcome Measures :

1. 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).

Biospecimen Retention:   None Retained

Samples are being stored

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 90 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• 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.

Criteria

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.

Contacts and Locations

Locations

United States, California

UCLA Division of Geriatric Psychiatry, Semel Institute

Los Angeles, California, United States, 90095

Sponsors and Collaborators

University of California, Los Angeles

Investigators

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

  Study Documents (Full-Text)

Documents provided by Gary Small, MD, University of California, Los Angeles:

Study Protocol and Statistical Analysis Plan  [PDF] December 3, 2018

More Information

Publications of Results:

Small GW, Kepe V, Siddarth P, Ercoli LM, Merrill DA, Donoghue N, Bookheimer SY, Martinez J, Omalu B, Bailes J, Barrio JR. PET scanning of brain tau in retired national football league players: preliminary findings. Am J Geriatr Psychiatry. 2013 Feb;21(2):138-44. doi: 10.1016/j.jagp.2012.11.019. Epub 2013 Jan 22.

Barrio JR, Small GW, Wong KP, Huang SC, Liu J, Merrill DA, Giza CC, Fitzsimmons RP, Omalu B, Bailes J, Kepe V. In vivo characterization of chronic traumatic encephalopathy using [F-18]FDDNP PET brain imaging. Proc Natl Acad Sci U S A. 2015 Apr 21;112(16):E2039-47. doi: 10.1073/pnas.1409952112. Epub 2015 Apr 6. Erratum in: Proc Natl Acad Sci U S A. 2015 Jun 2;112(22):E2981.

Chen ST, Siddarth P, Merrill DA, Martinez J, Emerson ND, Liu J, Wong KP, Satyamurthy N, Giza CC, Huang SC, Fitzsimmons RP, Bailes J, Omalu B, Barrio JR, Small GW. FDDNP-PET Tau Brain Protein Binding Patterns in Military Personnel with Suspected Chronic Traumatic Encephalopathy1. J Alzheimers Dis. 2018;65(1):79-88. doi: 10.3233/JAD-171152.

Omalu B, Small GW, Bailes J, Ercoli LM, Merrill DA, Wong KP, Huang SC, Satyamurthy N, Hammers JL, Lee J, Fitzsimmons RP, Barrio JR. Postmortem Autopsy-Confirmation of Antemortem [F-18]FDDNP-PET Scans in a Football Player With Chronic Traumatic Encephalopathy. Neurosurgery. 2018 Feb 1;82(2):237-246. doi: 10.1093/neuros/nyx536.

Other Publications:

Omalu BI, DeKosky ST, Hamilton RL, Minster RL, Kamboh MI, Shakir AM, Wecht CH. Chronic traumatic encephalopathy in a national football league player: part II. Neurosurgery. 2006 Nov;59(5):1086-92; discussion 1092-3.

Omalu BI, DeKosky ST, Minster RL, Kamboh MI, Hamilton RL, Wecht CH. Chronic traumatic encephalopathy in a National Football League player. Neurosurgery. 2005 Jul;57(1):128-34; discussion 128-34.

Guskiewicz KM, Marshall SW, Bailes J, McCrea M, Harding HP Jr, Matthews A, Mihalik JR, Cantu RC. Recurrent concussion and risk of depression in retired professional football players. Med Sci Sports Exerc. 2007 Jun;39(6):903-9.

Guskiewicz KM, Marshall SW, Bailes J, McCrea M, Cantu RC, Randolph C, Jordan BD. Association between recurrent concussion and late-life cognitive impairment in retired professional football players. Neurosurgery. 2005 Oct;57(4):719-26; discussion 719-26.

Omalu BI, Bailes J, Hammers JL, Fitzsimmons RP. Chronic traumatic encephalopathy, suicides and parasuicides in professional American athletes: the role of the forensic pathologist. Am J Forensic Med Pathol. 2010 Jun;31(2):130-2. doi: 10.1097/PAF.0b013e3181ca7f35.

Small GW, Kepe V, Ercoli LM, Siddarth P, Bookheimer SY, Miller KJ, Lavretsky H, Burggren AC, Cole GM, Vinters HV, Thompson PM, Huang SC, Satyamurthy N, Phelps ME, Barrio JR. PET of brain amyloid and tau in mild cognitive impairment. N Engl J Med. 2006 Dec 21;355(25):2652-63.

Small GW, Siddarth P, Burggren AC, Kepe V, Ercoli LM, Miller KJ, Lavretsky H, Thompson PM, Cole GM, Huang SC, Phelps ME, Bookheimer SY, Barrio JR. Influence of cognitive status, age, and APOE-4 genetic risk on brain FDDNP positron-emission tomography imaging in persons without dementia. Arch Gen Psychiatry. 2009 Jan;66(1):81-7. doi: 10.1001/archgenpsychiatry.2008.516.

Kepe V, Ghetti B, Farlow MR, Bresjanac M, Miller K, Huang SC, Wong KP, Murrell JR, Piccardo P, Epperson F, Repovs G, Smid LM, Petric A, Siddarth P, Liu J, Satyamurthy N, Small GW, Barrio JR. PET of brain prion protein amyloid in Gerstmann-Sträussler-Scheinker disease. Brain Pathol. 2010 Mar;20(2):419-30. doi: 10.1111/j.1750-3639.2009.00306.x. Epub 2009 Jun 9.

• Responsible Party: Gary Small, MD, Principal Investigator, University of California, Los Angeles
• ClinicalTrials.gov Identifier: NCT02003183
• Other Study ID Numbers: 11-001077; IND 74944 ( Other Identifier: FDA )
• First Posted: December 6, 2013
• Results First Posted: November 27, 2019
• Last Update Posted: March 3, 2020
• Last Verified: February 2020

Keywords provided by Gary Small, MD, University of California, Los Angeles:

Chronic Traumatic Encephalopathy; Traumatic Brain Injury; Cognitive Impairment; Positron Emission Tomography; [F-18]FDDNP

Additional relevant MeSH terms:

Brain Injuries; Brain Injuries, Traumatic; Brain Diseases; Chronic Traumatic Encephalopathy; Wounds and Injuries; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Brain Injury, Chronic; Neurodegenerative Diseases