Traumatic Brain Injury and Risk for Chronic Traumatic Encephalopathy
Condition: CTE; TBI (Traumatic Brain Injury)
MeSH terms: Brain Injuries; Brain Injuries, Traumatic; Brain Diseases; Chronic Traumatic Encephalopathy
Study type: Observational

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.
    

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).
    

Intervention name(s): [F-18]FDDNP
Intervention type(s): Radiation
Intervention description(s): Each participant was injected with [F-18]FDDNP, a radiolabeled molecular imaging probe, prior to receiving a PET scan.
Observational model: Cohort
Time perspective: Cross-Sectional
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.
      
Biospecimen description: 
      Samples are being stored
    
Keywords: Chronic Traumatic Encephalopathy; Traumatic Brain Injury; Cognitive Impairment; Positron Emission Tomography; [F-18]FDDNP