Traumatic Brain Injury and Risk for Chronic Traumatic Encephalopathy

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.

Background:

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.

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.