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.

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).

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.

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.

All participants had suspected CTE because of a history of traumatic brain injury and cognitive and/or mood symptoms. Of the 24 participants, 2 were lost to follow up and not included in the data analysis.

6 weeks

Although the participants groups were matched for important variables, these results need interpretation with caution given the relatively small sample sizes. Differences in cerebrovascular health and other variables also could influence the results.