Developing Therapies for Traumatic Brain Injury

Traumatic brain injury (TBI) is the leading cause of death and disability in people under age
45 in industrialized countries, but there is no specific treatment available for TBI.
Circulating endothelial progenitor cells (EPC) are markers of vascular injury that are
mobilized after signaling with cytokines, interleukins, MMP9 and other biomarkers (BM) that
may be detected in blood. However, the relation of EPC and these BM to TBI severity has not
been quantified. MRI measurements of lesion volume provide an objective method for TBI
severity assessment and outcome prediction. Moreover, diffusion tensor imaging (DTI) is
sensitive to detect TBI-related axonal injury, and PET (positron emission tomography) is
useful in functional interpretation of image findings. This cross-sectional study aims to
determine whether EPC and other BM are associated with MRI, DTI and PET findings, and with
functional outcomes in TBI patients.

OBJECTIVES:

The primary objective of the study is to evaluate levels of EPC and other BMs participating
in EPC mobilization in TBI patients in comparison to the healthy volunteers and to the
non-TBI trauma controls. The second objective is to relate EPC and BM levels to TBI severity
quantified by functional and radiological evaluations (MRI, DTI and PET). The third objective
is to determine, if there is a relationship between the level of EPC and other BM and
functional outcomes.

POPULATION:

100 male or female participants between 18 and 70 years of age will be enrolled within 30
days of a moderate TBI (classified as Glasgow Coma Scale (GCS) of 9-12) or mild TBI (GCS
13-15). If participants had post-traumatic amnesia (PTA) it must have lasted less than 7 days
and any loss of consciousness (LOC) must have lasted less than 24 hours. Fifty healthy
volunteers and 50 persons with non-TBI injuries (such as broken bones, orthopedic injuries or
surgery) will be enrolled.

RESEARCH DESIGN:

Before participating in this protocol, TBI and non-TBI injured participants must have
received routine clinical evaluations for their injuries in hospitals, doctors offices or
other medical facilities. They may be referred to the NIH Clinical Center after discharge or
they may be self-referred. They must be willing to have their medical records sent to the NIH
to assure that their injuries fit the protocol inclusion criteria. Healthy volunteers may be
recruited from families of other participants but most will be recruited through the NIH
Patient Recruitment and Public Liaison Office (PRPL).

This is an outpatient, observational study. Eligible participants will come to the NIH for
two 1 1/2 day outpatient visits separated by 30 days. Persons with TBI will have the same
tests at each of their two visits: a history and physical exam, electrocardiogram, research
blood draws (no more than 75 ml each visit), pregnancy and HIV testing, neuropsychological
testing, head magnetic resonance imaging (MRI) scan, and positron emission tomography scan
(PET scan). Healthy controls and persons with non-TBI injuries will have the same tests at
visit 1 as listed above. At visit 2, they will have all the same tests except they will not
have brain MRIs or PETs.

IMPORTANCE:

This study will provide novel data regarding the association of levels of EPC and the blood
BMs with severity of imaging-positive TBI. This study will provide a foundation for the
development of interventional trials aiming to improve neovascularization in TBI patients.

- INCLUSION CRITERIA FOR TBI PATIENTS:

To be included, TBI patients must meet all of the following criteria:

- Between 18 and 70 years of age

- Had head injury within the previous 30 days.

- Had a moderate TBI classified as GCS 9-12 or a mild TBI classified as GCS 13-15 at the
first ER or other medical examination. If LOC existed, it may not have lasted more
than 24 hours. If PTA existed it may not be more than 7 days.

- Admitted to an inpatient unit, ED, and/or evaluated in a doctors' office because of
head trauma.

- Injury occurred less than 30 (plus 5) days before enrollment

- Willingness to provide permission to allow release of medical records related to these
injuries.

INCLUSION CRITERIA FOR HEALTHY VOLUNTEERS:

Healthy volunteers will be eligible for enrollment if they meet the following inclusion
requirements:

- Between 18 and 70 years of age

- Determined to be healthy at the time of screening

- No known previous TBI, even mild (characterized as GCS >13, PTA < 1 day LOC < 30 min)

INCLUSION CRITERIA FOR NON-TBI TRAUMA CONTROLS:

Non-TBI trauma controls will be eligible for enrollment if they meet the following
criteria:

- Between 18 and 70 years of age

- Evaluated in an emergency department or in a physician s office or admitted to an
inpatient unit because of isolated traumatic injury resulting in a fracture (e.g,
limbs, ribs) or other orthopedic injury (ligament, tendon or joint injury) or non-life
threatening condition requiring surgery (appendectomy, etc.).

- No known previous TBI, even mild (characterized as GCS > 13, PTA < 1 day LOC < 30 min)

- Evaluated within 30 (plus 5) days after the trauma

- Willingness to provide permission to allow release of medical records related to these
injuries.

EXCLUSION CRITERIA FOR ALL STUDY PARTICIPANTS:

Study participants will be excluded from the study if he/she has one or more of the
following:

- Are not able to read and understand English to complete outcome assessments and
neurological scales

- Progressive or unstable disease of any body system including cardiovascular,
pulmonary, gastrointestinal, central nervous system, psychiatric, endocrine,
hematologic, renal, or immunologic disorders

- Alcohol dependence/substance abuse history within the past 5 years

- Known acute and chronic inflammatory disease (i.e. rheumatoid arthritis, systemic
lupus erythematosus, hepatitis, cirrhosis, sepsis, severe periodontosis or HIV
infection or AIDS.

- Clinically significant abnormal ECG, or acute myocardial infarction within last 3
months

- Ischemic or hemorrhagic stroke within last 3 months

- History of diabetes

- Currently undergoing evaluation or treatment for chronic illness or presenting with
symptoms suggestive of undiagnosed disorders

- Pregnant or lactating women

EXCLUSION CRITERIA FOR BRAIN MRI:

Of the participants and volunteers enrolled under the listed inclusion/exclusion, the
following will not be eligible for MRI scanning but will undergo all other study
procedures:

- Contraindication to MRI scanning, including certain metal implants or any other device
such as: cardiac pacemaker, insulin infusion pump, implanted drug infusion device,
cochlear, otologic, or ear implant, transdermal medication patch (nitroglycerine), any
metallic implants or objects, body piercing(s), bone/joint pin, screw, nail, plate,
wire sutures or surgical staples, shunts, cerebral aneurysms clips, shrapnel or other
metal imbedded in a participant s body (such as from war wounds or accidents or
previous work in metal fields or machines that may have left any metallic fragments in
or near the participant s eyes)

- Previous trauma or accidents in the past with non-certainty that metal objects are
still present in the body

- A condition precluding entry into the scanner (e.g. morbid obesity or claustrophobia)

- Pregnant women or women who are breast-feeding.

- Inability to lie flat on back for up to 90 minutes

EXCLUSION CRITERIA FOR BRAIN PET:

- A condition precluding entry into the scanner (e.g. morbid obesity or claustrophobia)

- Pregnancy or breast-feeding

- Blood glucose over 200 mg/dL when measured before the PET scanning

- Previous radiation exposure where the additional exposure from the PET scan would
exceed NIH annual limits