Developing Therapies for Traumatic Brain Injury
Developing Therapies for Traumatic Brain Injury
Background:

 - A person who has a traumatic brain injury (TBI) -- also called concussion -- can have
 serious and long-lasting effects. Doctors who treat TBI need more information about how the
 brain changes over time in people with TBI and how well a person recovers from it. To make
 existing TBI treatments more effective and develop new ones, researchers want to look more
 closely at how TBI affects people both physically and psychologically.

 Objectives:

 - To collect medical information from people with recent traumatic brain injury and compare
 this information to that of healthy volunteers and of persons who have had injuries to other
 parts of their bodies besides their heads (such as broken bones, orthopedic injuries, after
 surgery).

 Eligibility:

 3 groups of people between the ages of 18 and 70 years will be asked to take part.

 -  Persons who have had a traumatic brain injury (or concussion ) within the past 30 days,
 OR

 -  Persons who are healthy and have never had a traumatic brain injury, OR

 -  Persons who have had an injury within the past 30 days to a part of their body other
 than the head (such as a broken bone, orthopedic injury, surgery)

 Design:

 -  This study requires two outpatient visits each lasting 1 1/2 days. The 2 visits will be
 about 30 days apart. Persons with TBI and non-TBI injuries must have their first visit
 within 30 days of their injury.

 -  Screening: Participants will be screened with a medical history, physical examination,
 blood tests and electrocradiogram (ECG a routine heart test).

 -  The research will involve:

 1. Giving blood samples (no more than 75 ml each visit).

 2. Having tests of memory, attention, concentration, and thinking (neuropsychological
 testing).

 3. Having imaging studies of the head including magnetic resonance imaging (MRI) and
 positron emission tomography (PET) scans.

 -  Persons with TBI will have the same tests at Visit 1 and 2. Healthy controls and persons
 with non-TBI injuries will have the same tests at Visit 1 as listed above. But, at Visit
 2, they will not have brain MRIs or PETs.

 -  No treatments will be provided as part of this research protocol.
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