Translocator Protein and Inflammation After Traumatic Brain Injury

Objective:

Brain damage following traumatic injury (TBI) results from both direct (eg, mechanical injury
to the brain and vasculature) and indirect mechanisms (eg, secondary mechanisms such as
inflammation). While CT and MRI can help visualize the result of inflammatory processes in
the brain for instance, the development of cerebral edema neither method can be used to
document active inflammation itself. The translocator protein (TSPO), which is highly
expressed in microglia and reactive astrocytes, has been used as a biomarker in positron
emission tomography (PET) to identify active inflammatory processes. Recently, our laboratory
developed PBR28, a new PET ligand that images TSPO with high levels of specific binding. We
have successfully used PBR28 to investigate a number of brain disorders such as epilepsy,
multiple sclerosis, and HIV infection with minor cognitive motor disorder, and are detecting
neuroinflammation. The current protocol aims to explore whether PBR28 PET imaging can show
changes in subjects with TBI who have shown MRI abnormalities in the acute phase and also in
those who are in the chronic phase of TBI.

Study population: The following three groups will be studied:

TBI subjects who had brain injury within approximately 3 months and have exhibited MRI
abnormalities consistent with TBI and who are enrolled in "Evaluation, Pathogenesis, and
Outcome of Subjects with or Suspected Traumatic Brain Injury" (10-N-N122, PI Latour),
"Evaluation and Diagnosis of Potential Research Subjects with Traumatic Brain Injury (TBI),
(11-N-0084, PI: Lawrence Latour), or other CNRM protocols. N = 20

TBI subjects who had brain injury more than approximately 5 month ago, are enrolled in
11-N-0084, and meet criteria of TBI established by CNRM. N = 20

Healthy age-matched volunteers. N = 20.

Design:

This is an exploratory study to determine whether PBR28 can detect the increased TSPO
associated with neuroinflammation by scanning subjects who have shown MRI abnormalities in
the acute phase. We also investigate whether PBR28 detects changes in the chronic phase as
recently reported using an old ligand, PK 11195. Two groups of TBI subjects will be studied
depending on their availability relative to the time of injury. To investigate changes in
TSPO in the areas of MRI abnormalities in the acute phase, one group of TBI subjects (n = 20)
will be studied who have shown TBI- related MRI abnormalities. These participants will have
up to four PBR28 PET scans; one to two PET scans within approximately 10 days of head injury,
a third PET scan approximately three months after injury, and a fourth scan approximately one
year after the scan at ~three months. To study changes in TSPO in the chronic phase, another
group of TBI subjects will be enrolled who had brain injury more than approximately 5 months
but within 5 years ago and meet the criteria of TBI by CNRM. This separate group is included
because some TBI subjects are being recruited by CNRM only sometime after the injury. The
participants at the chronic phase will have one PET and one MRI scan. In addition to MRI
data, for all TBI subjects, clinical information obtained in 10-N-N122 (only the acute phase)
and 11-N-0084 (both acute and chronic phase) will be used to evaluate the utility of the PET
data in order to better understand the pathology of TBI.

Outcome Measures:

In this exploratory study to investigate the ability of PBR28 PET to detect increases in
TSPO, the primary goal will be to measure the magnitude and variance of any increases
observed in PBR28 binding in areas of inflammation following TBI. Those data may be used to
design future studies with a larger sample size.

- INCLUSION CRITERIA:

Subjects with TBI:

Subjects with TBI eligible for participation in this research study must meet the following
inclusion criteria. Depending on the timing of the availability of the subjects the
following two groups will be studied. No subject will be enrolled in both group 1 and 2.

Group 1 Acute/subacute phase (n = 20)

- Diagnosis of non-penetrating TBI caused by a head injury within approximately 5
months.

- Ambulatory.

- Able to provide self consent without a legally-authorized representative based on the
assessment of the Decision Making Capacity (DMC) by the Human Subjects Protection Unit
(HSPU).

- Show abnormal MRI findings consistent with TBI in protocol 10-N-N122 or in the image
database of the CNRM Image Processing Core if the subject is recruited from CNRM
Recruitment Core protocol 11-N-0084 or another CNRM protocol that allows referrals to
other studies.

- Age 18 or older.

Group 2 Chronic phase (n = 20)

- A head injury approximately 5 months 5 years ago.

- Enrolled in CNRM Recruitment Core protocol 11-N-0084 or another CNRM protocol that
allows referral to other studies..

- Meet at least one of the criteria of Probable or Definite TBI established by CNRM.

- Ambulatory.

- Able to provide self consent without a legally-authorized representative based on the
assessment of the Decision Making Capacity (DMC) by the Human Subjects Protection Unit
(HSPU).

- Age 18 or older.

Group 3 Healthy subjects.

- Healthy without past or present history of brain disease.

- Age 18 or older.

EXCLUSION CRITERIA:

Subjects with TBI for both groups 1 and 2 are not eligible for participation in this
research study if any of the following conditions exist:

1. Present or past history of brain disease other than TBI.

2. Subjects with abnormal MRI findings that suggest a diagnosis other than TBI or a
second lesion such as brain tumor in addition to the changes consistent with TBI.

3. Serious medical conditions, which make study procedures of the current study unsafe.
Such serious medical conditions include uncontrolled epilepsy and multiple serious
injuries. The Medical Advisory Investigator of this protocol will determine whether
the subject needs to be excluded.

4. Contraindication to MRI scanning including certain metal implants or devices such as:
cardiac pacemaker, insulin infusion pump, implanted drug infusion device, cochlear,
otologic, or ear implant, transdermal medication patch (Nitroglycerine) that cannot be
removed for the study, 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 subject 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
subject s eyes).

5. Conditions precluding entry into the scanners (e.g. morbid obesity, claustrophobia,
etc.).

6. In female subjects, pregnancy or breastfeeding.

7. Exposure to research related radiation in the past year that, when combined with this
study, would place subjects above the allowable limits.

HEALTHY SUBJECTS ARE NOT ELIGIBLE FOR PARTICIPATION IN THIS RESEARCH IF ANY OF THE
FOLLOWING CONDITIONS EXIST:

1. Any past or present history of DSM Axis I disorder, with the exception of substance
abuse that ended over 6 months prior to enrollment.

2. Contraindication to MRI scanning including certain metal implants or devices such as:
cardiac pacemaker, insulin infusion pump, implanted drug infusion device, cochlear,
otologic, or ear implant, transdermal medication patch (Nitroglycerine) that cannot be
removed for the study, 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 subject 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
subject s eyes).

3. Conditions precluding entry into the scanners (e.g. morbid obesity, claustrophobia,
etc.).

4. In female subjects, pregnancy or breastfeeding.

5. Clinically significant laboratory abnormalities, as defined as laboratory values that
are out of normal range or require clinical workup and/or treatment.

6. Exposure to research related radiation in the past year that, when combined with this
study, would place subjects above the allowable limits.

7. Previously determined as a low-affinity binder in another study on TSPO.

8. Positive results of urine drug screen on enrollment.

HIV positive subjects are considered healthy as long as he/she does not show neuological or
psychiatric symptoms based on history and physical exams. Results of HIV test in both TBI
subjects and healthy controls may help interpretation of the PET results. Statistical
analysis: Analysis of date/study outcomes. Results of urine drug screen and history of
using drugs of abuse may also help interpretation of the PET results. In addition,
inclusion of TBI subjects who show positive for urine drug screen may improve recruitment
of TBI subjects.