Conditions: Traumatic Brain Injury (TBI) Healthy
Keywords: Positron Emission Tomography (PET) Inflammation Microglial Activation Traumatic Brain Injury TBI
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 52
Healthy volunteers: yes

Brief summary:
Background:

\- People with traumatic brain injury (TBI) often have inflammation in the brain. A protein called the translocator protein (TSPO) is often present with inflammation. Researchers want to see if a radioactive chemical known as \[11C\]PBR28 can be used to study TSPO and inflammation in the brain of people with TBI.

Objectives:

\- To test whether \[11C\]PBR28 can be used to study changes in the brain after a traumatic brain injury.

Eligibility:

* Individuals at least 18 years of age who have had TBI and have had a brain scan that shows signs of inflammation.
* Healthy volunteers at least 18 years of age.

Design:

* Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected.
* All participants will have two brain scans during an outpatient visit. A magnetic resonance imaging scan will study brain activity. A positron emission tomography (PET) scan will use \[11C\]PBR28 to look for signs of TSPO and brain inflammation.
* Participants with TBI will have two PET scans within 10 days of the head injury, and a PET scan around 90 days after the injury. They may also have MRI scans under this or another study. Tests of thinking, memory, and concentration will be used to study the effects of the injury and inflammation

Detailed description:
Objective:

Brain damage following traumatic injury (TBI) results from both direct (e.g., mechanical injury to the brain and vasculature) and indirect mechanisms (e.g., 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.

Arms:
arm 1: Single intravenous injection of \[C-11\]PBR28, \~10-20 mCi, prior to baseline brain positron emission tomography (PET) scan in Acute (\< 5 months post-injury) traumatic brain injury (TBI) patients. arm 2: Single intravenous injection of \[C-11\]PBR28, \~10-20 mCi, prior to repeat brain positron emission tomography (PET) scan in Acute (\< 5 months post-injury) traumatic brain injury (TBI) patients. arm 3: Single intravenous injection of \[C-11\]PBR28, \~10-20 mCi, prior to brain positron emission tomography (PET) scan in Chronic (5 months - 5 years post-injury) traumatic brain injury (TBI) patients. arm 4: Single intravenous injection of \[C-11\]PBR28, \~10-20 mCi, prior to brain positron emission tomography (PET) scan in Healthy Subjects.

Interventions: intervention 1: [11C]PBR28 and Positron Emission Tomography (PET)
Intervention descriptions: intervention 1: Brain PET with \[11C\]PBR28. 11C\]PBR28 is a new PET ligand that images TSPO with high levels of specific binding.

Protocol document:
Prot_SAP_000.pdf: 
 
CNS IRB Protocol Template (rev.3.25.10) 
 
 
1. Title Page 
Protocol Title: PET Imaging of Translocator Protein in Subjects with Traumatic Brain Injury 
Protocol Number 12-M-0063 
Date of This Submission/Version January 10, 2017 
 
Principal Investigator 
Masahiro Fujita, MD, PhD 
 
Medical Advisory Investigator 
Robert B. 
Innis, MD, 
PhD 
MIB/NIMH 
10/B1D43 
301-594-
1368 
robert.innis@nih.gov 
 
 
 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 2 of 48 
2. Table of Contents 
1. Title Page .................................................................................................................................... 1 
2. Table of Contents ........................................................................................................................ 2 
3. Précis ........................................................................................................................................... 4 
4. Introduction/ Scientific Rationale ............................................................................................... 5 
5. Study objectives or hypotheses ................................................................................................... 8 
6. Subjects ....................................................................................................................................... 9 
a. Study populations .................................................................................................................... 9 
b. Inclusion criteria ..................................................................................................................... 9 
c. Exclusion criteria .................................................................................................................. 10 
d. Eligibility Checklist .............................................................................................................. 11 
7. Study Design and Methods ....................................................................................................... 11 
a. Study phases .......................................................................................................................... 11 
i. 
Study overview ............................................................................................................... 11 
ii. 
Recruitment ................................................................................................................ 12 
iii. 
Screening methods ...................................................................................................... 12 
iv. 
Study design ............................................................................................................... 13 
v. 
Study procedures ........................................................................................................ 14 
vi. 
Follow-up/termination procedures ............................................................................. 18 
b. Relationship of this study to other protocols ........................................................................ 18 
c. Management of data and samples ......................................................................................... 19 
8. Risks/ discomforts ..................................................................................................................... 20 
9. Subject monitoring .................................................................................................................... 22 
10. Outcome measures .................................................................................................................. 23 
11. Statistical analysis ................................................................................................................... 23 
a. Analysis of data / study outcomes ......................................................................................... 23 
b. Criteria for significance, power analysis, and accrual number request ................................ 24 
12. Human Subjects Protection ..................................................................................................... 24 
a. Subject selection.................................................................................................................... 24 
b. Justification for inclusion / exclusion of children ................................................................. 24 
c. Justification for inclusion of other vulnerable subjects......................................................... 25 
d. Justification of sensitive procedures (use of placebo, medication withdrawal, provocative 
testing)....................................................................................................................................... 25 
e. Safeguards for vulnerable populations .................................................................................. 25 
f. Qualifications of investigators ............................................................................................... 25 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 3 of 48 
13. Benefits ................................................................................................................................... 27 
14. Summary / classification of risk ............................................................................................. 28 
15. Consent documents and process ............................................................................................. 28 
16. Data and Safety monitoring .................................................................................................... 29 
17. Quality Assurance ................................................................................................................... 30 
a. Quality assurance monitor..................................................................................................... 30 
b. Quality assurance plan .......................................................................................................... 30 
18. Reporting of Unanticipated problems, adverse events and protocol deviations ..................... 30 
19. Alternatives to participation or alternative therapies .............................................................. 30 
20. Privacy .................................................................................................................................... 30 
21. Confidentiality ........................................................................................................................ 31 
22. Conflict of Interest .................................................................................................................. 31 
23. Technology Transfer ............................................................................................................... 31 
24. Research and Travel Compensation........................................................................................ 31 
25. References ............................................................................................................................... 34 
26. Appendices .............................................................................................................................. 37 
1. Eligibility checklist ............................................................................................................... 37 
2. Brief explanation provided by investigators of protocol 10-N-N122 to TBI subjects as an 
advertisement ............................................................................................................................ 42 
3. MRI safety screening questionnaire...................................................................................... 43 
4. Biospecimin Repository Shipment Guidelines ..................................................................... 44 
5. Advertisement to Recruit Subjects with Traumatic Brain Injury ......................................... 46 
6. TBI Evidence Form by CNRM ............................................................................................. 47 
7. Sample Letter for Consent for Data and Sample Sharing of Previously Collected Data and 
Samples ..................................................................................................................................... 48 
 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 4 of 48 
3. Précis 
 
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 [11C]PBR28, a new PET ligand that images TSPO with high levels of 
specific binding. We have successfully used [11C]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 
[11C]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: 
1) TBI subjects who had brain injury within ~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 
2) TBI subjects who had brain injury more than ~5 month ago, are enrolled in 11-N-0084 or 
other CNRM protocols, and meet criteria of TBI established by CNRM. N = 20 
3)  Healthy age-matched volunteers. N = 20. 
Design: This is an exploratory study to determine whether [11C]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 [11C]PBR28 detects changes in the 
chronic phase as recently reported using an old ligand, [11C]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 [11C]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 ~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. If the TBI subject is 
recruited from another protocol under CNRM, the clinical information obtained under the 
CNRM protocol will be used for 12-M-0063 as long as both the CNRM protocol and the TBI 
subject allow. 
Outcome Measures: In this exploratory study to investigate the ability of [11C]PBR28 PET to 
detect increases in TSPO, the primary goal will be to measure the magnitude and variance of any 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 5 of 48 
increases observed in [11C]PBR28 binding in areas of inflammation following TBI. Those data 
may be used to design future studies with a larger sample size. 
 
4. Introduction/ Scientific Rationale 
Traumatic brain injury 
 
Each year, at least 1.4 million people sustain TBI, with over 1.1 million treated and 
released from the emergency department (Langlois et al., 2006). Annually, approximately 
125,000 patients with TBI—typically those whose injuries are more severe—experience 
permanent disability as a result of damage to the brain (Selassie et al., 2008; Zaloshnja et al., 
2008). In contrast, mild TBI, which accounts for at least 75% of all TBI cases, results in more 
subtle functional and cognitive deficits that often go undetected in the acute setting. Over time, 
these patients can experience drastic changes in their quality of life (Pierce & Hanks, 2006), find 
it difficult to resume daily activities, and may be unable to return to work for weeks or months 
(Wagner et al., 2002). 
The vast majority of TBI research and clinical care uses a three level system to classify 
the severity of the injury (mild, moderate, severe); this system has not changed in decades. It is 
based on subjective reports of symptoms, duration of loss of consciousness, post-traumatic 
amnesia, and the Glasgow Coma Scale (GCS). While the current taxonomy is effective for the 
acute assessment of injury and is a good predictor of mortality, it tells us little about long term 
prognosis and other key factors (e.g., the likelihood of regaining functional independence, 
resuming work, or participating in the community) (Conzen et al., 1992) (Green et al., 2008). In 
addition, the taxonomy does not take advantage of newer methodologies that might aid in 
classification, including imaging, serum biomarkers, and neuropsychological testing. Including 
these variables might add significant predictive power to any outcome model. 
 
This study was initially sponsored by the Center for Neuroscience and Regenerative 
Medicine (CNRM) and received CNRM funds directly for the conduct of the study. CNRM 
sponsorship for the study has ended. The study will, however, continue in collaboration with 
CNRM. Under this collaboration, the study will continue to use CNRM Core Resources 
including the Acute, Recruitment, Phenotyping, and Imaging Cores which encompass CNRM-
supported scanners and image analysis resources. In addition, data without PII will continue to 
be shared with CNRM and stored in the CNRM Data Repository. 
 
Traumatic brain injury and inflammation 
 
Brain damage following traumatic injury results from the primary mechanical injury 
followed by secondary inflammatory tissue reactions. The initiation and progression of 
inflammation in TBI are complex and multifactorial issues encompassing pro- and anti-
inflammatory cytokines, chemokines, adhesion molecules, complement factors, reactive oxygen 
and nitrogen species, and other undefined factors. While the extant evidence suggests that 
inflammation can have both beneficial and detrimental effects in TBI, the mechanisms 
underlying this dichotomy are mostly unknown. Because animal studies have shown that 
modifying inflammatory response is neuroprotective (Cernak et al., 2001) (Lloyd et al., 2008), 
monitoring inflammation may provide critical information for successfully treating patients with 
TBI. 
 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 6 of 48 
MRI in acute phase of traumatic brain injury 
Preliminary MRI data emerging from the first 100 subject enrolled under protocol 10-N-
N122 indicate trauma-related pathology evolve over the first week.  Within the first 48 hours of 
injury, evidence of both cytotoxic and vasogenic edema appear on diffusion weighted imaging 
(DWI) and T2-FLAIR.  Extravascular blood or thrombosis is seen on susceptibility weighted 
imaging.  On post-contrast FLAIR, enhancement of the meninges and subdural space occur in 
close to half of the subjects imaged.  The dynamic evolution of many of the markers over the 
first week suggests first, that the pathology is temporally correlated with the injury and is not 
incidental, and second, that the pathology may be part of an active inflammatory response.  By 
three months, many of the markers are no longer visible; either a plateau has been reached, 
pathology has reversed or recovered, or in some cases, permanent damage to the parenchyma, as 
evidenced by necrosis and atrophy on high resolution T1 imaging, has occurred.  Data between 
one week, and three months are lacking.  It is also not clear that injury is limited to the focal 
lesions that are event on MRI.  While the data points toward a time-course of inflammation that 
transpires in the period of a few weeks, the optimal time for detecting the injury by specifically 
imaging a marker of inflammation using PET is not known. 
 
Traumatic brain injury and translocator protein (TSPO) 
 
Translocator protein (TSPO; formerly known as peripheral benzodiazepine receptor) is an 
ion-channel type receptor existing in the mitochondrial outer membrane. Because TSPO is 
highly expressed in activated microglia and reactive astrocytes, TSPO has been used as a 
biomarker in positron emission tomography (PET) studies. In addition to being a biomarker of 
neuroinflammation in general, TSPO may be strongly linked to biological reactions and 
pathological changes in TBI because TSPO is expressed in mitochondria; mitochondria, in turn, 
provide most of the high energy consumption caused by tissue reactions to brain trauma. In 
addition, Ro5-4864, a ligand binding to TSPO, showed neuroprotective effects in a rat model of 
TBI (Soustiel et al., 2008), and a PET study of a rat model of TBI showed increased TSPO (Yu 
et al., 2010). 
 
PET imaging of Translocator protein 
 
PET imaging of TSPO is the most widely used method to image neuroinflammation in 
vivo. Our laboratory developed two promising radioligands—[11C]PBR28 and [18F]PBR06—that 
selectively bind to TSPO and that have a much greater specific signal than the prototypical agent, 
[11C]PK 11195. After confirming high levels of specific binding in monkey (Imaizumi et al., 
2007a; Imaizumi et al., 2008), demonstrating successful detection of increased TSPO in a rat 
model of cerebral infarction (Imaizumi et al., 2007b), and establishing a method of quantification 
in healthy humans (Fujita et al., 2008), we initiated the following studies in a number of brain 
diseases, and are obtaining promising results. 
1) Stroke. We identified an incidental lacunar stroke in an otherwise healthy individual, 
showing that [11C]PBR28 is sensitive enough to detect even small focal changes (Kreisl et al., 
2009). 
2) Epilepsy. We used [11C]PBR28 to study 16 subjects with unilateral temporal lobe 
epilepsy and seven healthy subjects using a high-resolution research tomograph (Hirvonen, 
submitted). Compared to healthy controls, epileptic subjects had a 10% higher brain uptake in 
the entire hippocampus ipsilateral to the seizure focus. 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 7 of 48 
3) HIV infection. This study, conducted in collaboration with Justin McArthur (Johns 
Hopkins) was designed to measure brain inflammation in vivo in healthy HIV-seronegative 
controls, cognitively normal HIV-seropositive subjects, and HIV-seropositive subjects with 
minor cognitive motor disorder (MCMD). Our preliminary results found that seronegative 
controls (N=8) had significantly greater [11C]PBR28 uptake than seropositive controls (N=7), 
and that MCMD subjects (N=7) showed a trend towards greater uptake than seropositive 
controls.  
4) Multiple sclerosis. In 11 subjects with multiple sclerosis, a focal increase in 
[11C]PBR28 binding was observed in the areas of gadolinium-enhanced lesions (Figure below). 
In addition, in a small number of cases, increased [11C]PBR28 binding preceded the appearance 
of gadolinium-enhancement, indicating early glial activation in multiple sclerosis lesions (Oh et 
al.). 
 
Figure. Increase of [11C]PBR28 binding in multiple sclerosis 
 
As described above, the preliminary results of protocol 10-N-N122 suggest the 
involvement of neuroinflammation in TBI. In addition, recent studies using [11C]PK 11195 
showed increase in TSPO in patients 0.5 – 17 years after injury (Folkersma et al., 2011; 
Ramlackhansingh et al., 2011) but we showed that [11C]PK 11195 has low levels of specific 
binding (Kreisl et al., 2010) and their quantification may have errors because of not obtaining 
arterial blood data. Therefore, in the current protocol, we intend to detect neuroinflammation 
using [11C]PBR28, which selectively binds to a marker of neuroinflammation, TSPO with high 
specific binding.  
 
High-, Low-, (Non-), and Mixed-Affinity Binders 
 
Initial studies found that some individuals—hereafter referred to as non-binders— 
showed no detectable binding in [11C]PBR28 PET scans (Kreisl et al., 2010). Subsequently, a 
postmortem study reported the presence of binding sites with two different affinity levels to 
PBR28 and some other PET ligands; thus, there appear to be three distinct groups based on 
affinity: high-, mixed-, and low-affinity binders (also known as non-binders) (Owen et al., 2010) 
(Owen et al., 2011). Low-affinity binders have TSPO with only low affinity binding sites. 
Mixed-affinity binders have TSPO with both high- and low-affinity binding sites. High-affinity 
binders have TSPO with only high-affinity binding sites. [11C]PBR28 PET data of individual 
subjects demonstrated that low-affinity binders are clearly identified, but that it is difficult to 
differentiate high- and mixed-affinity binders. Our laboratory has conducted more [11C]PBR28 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 8 of 48 
scans than any other group in the world. When all subjects in our database were combined, 
13/149 (8.7%) subjects were classified as low-affinity binders; however, no discerning features 
have been found to identify low-affinity binders among healthy volunteers or patients. We are 
presently unable to state whether individual neuropsychiatric disorders are prone to different 
distributions of low-affinity binders, because the number of subjects within each disease 
category is too small. 
 
In the current protocol, TBI subjects in acute/subacute phase (group 1 in section 6.b. 
Inclusion criteria) will have one or two [11C]PBR28 scans within approximately 10 days of 
injury. All TBI subjects including those who participate within ~10 days of brain injury will have 
a blood sampling to determine the affinity status to PBR28. The first PET scan will be performed 
without having results on the affinity status determined by in vitro binding or genetic assay. 
Based on our previous observations, we expect that approximately ~10% will be low-affinity 
binders, who will thus be excluded from the data analysis. If the first PET scan indicates that the 
TBI subject is a low-affinity binder, no further scan will be performed. The first PET scan within 
~10 days of brain injury will be performed without knowing the affinity status of TSPO because 
to obtain scientifically valuable data, the [11C]PBR28 scans need to be performed within a timely 
manner once MRI abnormalities have been established in these TBI subjects. Furthermore, as 
stated above, the probability of encountering low-affinity binders is only ~10%. By waiting for 
the results on the affinity status before doing the first [11C]PBR28 brain scan, we will miss a 
chance to do a PET scan in a timely fashion to obtain scientifically valuable data. If the results of 
the first PET scan indicate that the subject is a low-affinity binder, no more PET scans will be 
performed on that subject. 
 
TBI subjects recruited from protocol 11-N-0084 or other CNRM protocols may 
participate in this PET imaging protocol only at the time point of approximately three months or 
later after the head injury. For these subjects, screening in vitro binding assay using leukocytes 
will be performed because there is no strong time constraint to conduct the scan within 
approximately 10 days, and because additional visits for blood drawing would not be a 
significant extra burden to the subjects. Low-affinity binders will not undergo a [11C]PBR28 
brain scan. 
For all healthy subjects, screening binding assays to detect low-affinity binders will be 
performed because these subjects do not need to have a brain PET scan within a certain time 
frame. Low-affinity binders will not undergo a [11C]PBR28 brain scan. 
For all subjects including TBI subjects who have PET scans within ~10 days and whose 
results on the affinity status will be available after the PET scans within ~10 days, the results of 
the affinity status will be used for post hoc analysis of the results. Such analyses are useful 
because as stated above, PET data itself does not differentiate high- and low-affinity binders. 
Only low affinity binders are clearly identified by PET. 
 
5. Study objectives or hypotheses 
 
This exploratory study aims to investigate the utility of PET TSPO imaging in TBI. 
Based on the literature and the preliminary results of protocol 10-N-N122 and literature reviewed 
above, we hypothesize that PET [11C]PBR28 imaging in TBI patients will show increased TSPO 
in the areas of brain injury due to inflammatory reactions. Pilot data obtained via the current 
study are needed to estimate the prevalence of PET positive imaging in subjects with TBI, in 
order to help design future hypothesis-driven studies with a larger sample size based on proper 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 9 of 48 
power calculations. Relationship between PBR28 binding and neurocognitive function will also 
be studied to obtain pilot data to design future studies. We will also attempt to compare the time 
course of the changes in PET and MRI and changes in TSPO in the chronic phase of TBI. 
 
6. Subjects 
a. Study populations 
The following three groups will be studied. 
 
Group 1 (n = 20): Subjects with a history of acute head injury and MRI scans showing TBI-
related changes.  
 
Group 2 (n = 20): Subject who had brain injury ~5 months – 5 years ago and meet criteria of TBI 
established by CNRM. 
 
Group 3 (n = 20): Age-matched healthy controls 
b. 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) 
1. Diagnosis of non-penetrating TBI caused by a head injury within ~5 months. 
2. Ambulatory. 
3. 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). 
4. 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. 
5. Age 18 or older. 
 
Group 2 Chronic phase (n = 20) 
1. A head injury ~5 months – 5 years ago. 
2. Enrolled in CNRM Recruitment Core protocol 11-N-0084 or another CNRM protocol 
that allows referral to other studies. 
3. Meet at least one of the criteria of Probable or Definite TBI established by CNRM. 
4. Ambulatory. 
5. 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). 
6.  Age 18 or older. 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 10 of 48 
 
Group 3 Healthy subjects. 
1. Healthy without past or present history of brain disease. 
2. Age 18 or older. 
c. 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 study 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.  


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 11 of 48 
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 neurological 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 (see section 11. 
Statistical analysis. a. Analysis of data / 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. 
 
d. Eligibility Checklist 
 
Eligibility checklist is attached as Appendix 1. 
7. Study Design and Methods 
a. Study phases 
i. 
Study overview 
To detect changes in TSPO, a marker of neuroinflammation, in both acute/subacute and 
chronic phases, the following three groups will be studied. All TBI subjects will be recruited 
from the participants in the CNRM Recruitment Core protocol 11-N-0084 (groups 1 and 2), 
protocol 10-N-N122 (group 1), and other CNRM protocols (groups 1 and 2) that allow referrals 
to other studies. 
 
Group 1 (n = 20): TBI in acute/subacute phase who have shown TBI-related MRI abnormalities 
under 10-N-N122, CNRM Image Processing Core, or other CNRM protocols that allow referrals 
to other studies will have up to four [11C]PBR28 PET scans to compare changes in PET and MRI 
scans.  
 
Group 2 (n = 20): TBI in chronic phage will have one [11C]PBR28 PET and one MRI scan 
between ~5 months and 5 years after injury. The participants need to meet at least one item of 
Probable or Definite TBI in the criteria established by CNRM (Appendix 6, section 24-6). The 
criteria have been established by CNRM based on guidance by researchers specialized in TBI. 
 
Group 3 (n = 20): Healthy controls. Healthy controls will be studied to compare [11C]PBR28 
binding in areas with normal MRI scans in TBI subjects and the binding in age-matched healthy 
controls. 
 
Medications are allowed for all PET scans of TBI subjects because currently no FDA-approved 
medication binds to TSPO as a therapeutic target and direct interactions between [11C]PBR28 
and medications are not expected. Treatment history will be obtained from CNRM Recruitment 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 12 of 48 
Core (groups 1 and 2) or protocol 10-N-N122 (group 1). If the TBI subject is referred from 
another CNRM protocol, treatment history will be obtained from the CNRM protocol as long as 
the protocol allows. For exploratory analysis, results of standardized and validated 
neuropsychological tests will be used to correlate PET findings with subjects’ 
neuropsychological function. 
ii. 
Recruitment 
TBI subjects: 
TBI subjects participating in protocol 10-N-N122 will be recruited from Suburban 
Hospital (Bethesda, Maryland). TBI subjects will also be recruited from subjects enrolled in 
CNRM Recruitment Core protocol 11-N-0084. TBI subjects will also be recruited from other 
CNRM protocols as long as those protocols allow referrals. For the participants of 10-N-N122, 
the PI (Lawrence L. Latour, PhD) or an AI of that protocol will do pre screening to determine the 
eligibility of TBI subjects (Appendix 1). With participant’s written consent, all research and 
medical information obtained in protocol 10-N-N122 will be shared. A 10-N-N122 investigator 
will provide the eligible TBI subject with a sheet briefly explaining the current protocol 
(Advertisements: Appendix 2 or 7), and ask if a study investigator of the current protocol can 
contact the subject. If the TBI subject agrees to be contacted, a study investigator of the current 
protocol will contact the subject and obtain consent based on the procedures described in Section 
15. TBI subjects can also contact our PET study team if they wish to initiate study participation. 
For participants of CNRM Recruitment Core protocol 11-N-0084, the PI or an AI of the 
present PET protocol will determine eligibility. 11-N-0084 has been approved to share subjects’ 
information with this PET protocol. If the participants are eligible to this PET protocol, a 
member of 11-N-0084 research team will initially contact the subject. Appendix 5 will be handed 
over to the TBI subjects. If the TBI subject agrees to be contacted, a study investigator of 12-M-
0063 will contact the subject and obtain consent based on the procedures described in Section 15. 
TBI subjects can also contact our PET study team if they wish to initiate study participation. 
The participants of other CNRM protocols that allow sharing information to determine 
the eligibility are treated in the same way as the participants of CNRM Recruitment Core 
protocol 11-N-0084 described in the previous paragraph. the PI or an AI of protocol 12-M-0063 
will determine the eligibility based on the inclusion and exclusion criteria of 12-M-0063. If the 
participants are eligible for 12-M-0063, a member of the research team of the original CNRM 
protocol will initially contact the subject. Appendix 5 will be handed over to the TBI subjects. If 
the TBI subject agrees to be contacted, a study investigator of 12-M-0063 will contact the subject 
and obtain consent based on the procedures described in Section 15. TBI subjects can also 
contact our PET study team if they wish to initiate study participation. 
 
 
Healthy subjects: 
 
Healthy volunteers meeting inclusion and exclusion criteria (above) will be recruited 
from the community and at the NIH through IRB approved advertisements in newspapers and 
newsletters, private physicians, and social service agencies. Healthy volunteers may be recruited 
from other NIMH Molecular Imaging Branch protocols. 
iii. 
Screening methods 
 
For TBI subjects participating in protocol 10-N-N122, the PI (Lawrence L. Latour, PhD) 
or an AI of that protocol will do pre screening to determine eligibility to participate in the current 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 13 of 48 
protocol. 10-N-N122 has been amended to allow the PI or an AI of that protocol to determine 
whether their participants are eligible to this PET protocol. The participants will then be 
scheduled for study procedures in a manner that will not interfere with the subject’s medical 
care. For participants of 11-N-0084 or other CNRM protocols, the PI or an AI of this PET 
protocol will determine eligibility based on shared information. The initial contact to the eligible 
subjects will be done by a member of the research team of the original protocol such as 11-N-
0084 and the CNRM protocols. 
 
For both TBI subjects and healthy subjects, screening assessments will include a 
diagnostic interview, neurological assessment, physical examination, lab work (Complete Blood 
Count (CBC), Complete Metabolic Panel (CMP), and urine analysis, urine toxicology screen). 
Screening will be done in the outpatient clinic/Day Hospital and will include a nursing 
assessment. For subjects with TBI, written consent will be obtained to use as much of this 
information as possible from protocol 10-N-N122 or from the CNRM. Some healthy subjects 
will be evaluated under the general screening protocol 01-M-0254. Screening procedures will not 
be repeated for healthy subjects if performed under the screening protocol within 12 months for 
diagnostic interview, neurological assessment, and physical examination, or six months for blood 
and urine tests. Otherwise, tests will be conducted as part of this study. Subjects will be screened 
for MRI safety using the screening questionnaire used by the Radiology and Imaging Sciences 
Program of the Clinical Center (Appendix 3). 
 
iv. 
Study design 
Group 1 (TBI in acute/subacute phase): This group will have [11C]PBR28 PET scans at up to 
four time points. We will attempt to perform two of these scans within approximately 10 days of 
head injury as long as they are willing to do two and the scheduling allows. Two PET scans will 
be attempted on all TBI subjects, both occurring within ~10 days of injury. While every effort 
will be made to obtain both scans, completion of the imaging assessment may not be possible 
due to limited availability of the scanner, off-hours staffing, and other key resources. The target 
time for the first PET scan will be 1-5 days following head injury.  The target time for the second 
PET scan will be 6-10 days. The minimal interval between two scans is 2 days, and the maximal 
interval is 7 days. If the TBI subjects are not willing to have two [11C]PBR28 scans or schedule 
does not allow, one PET scan will be performed. In addition, one PET scan will be conducted at 
approximately 90 days after injury (90 +/- 50 days) and the last PET scan will be conducted 
approximately one year (but not within one year) after the previous scan and within 5 years of 
injury. MRI scans at each time point will be performed under the current protocol or 10-N-N122. 
Clinical information will be obtained through protocol 10-N-N122 or CNRM. The end point of 
study enrollment is 5 years from brain injury. 
 
If the first PET scan performed within approximately 10 days of head injury indicates 
that the TBI subject is a low-affinity binder for PBR28, the study participation will be terminated 
and no further scan and other study procedure will be performed under this protocol. 
 
Group 2 (TBI in chronic phase): This group will have one [11C]PBR28 PET and one MRI scans. 
We will attempt to schedule the scans soon after receiving referrals from CNRM to avoid drop 
outs. Therefore, the timing of the scans in group 2 is determined by the timing of the referrals 
from CNRM. The end point of study enrollment is 5 years from brain injury. Clinical 
information will be obtained through CNRM. 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 14 of 48 
 
Group 3 (Healthy subjects): This group will have a screening visit, one [11C]PBR28 PET scan, 
and one MRI scan. If high resolution structural MRI was done within one year, an MRI scan may 
not be obtained under the current protocol. For healthy volunteers who have undergone 
[11C]PBR28 PET scanning under another NIMH Molecular Imaging Branch protocol, we will 
use the results from that scan for the purposes of this protocol. Therefore, these healthy 
volunteers will not undergo a PET scan for the this study 
v. 
Study procedures 
 
All procedures under the current protocol will be conducted for research, not clinical, 
purposes.  
 
Existing data collected on TBI subjects: 
 
Data collected on TBI subjects under protocol 10-N-N122 or via the CNRM will be 
shared with this protocol. During the consent process for 10-N-N122 or for the CNRM 
Recruitment Core protocol 11-N-0084, subjects will be informed that if they choose to 
participate, identifiable data and Protected Health Information (PHI) will be shared with the 
current PET protocol. For other CNRM protocols, the participants will be asked if they allow 
sharing identifiable data and PHI with other protocols such as 12-M-0063. The TBI subjects will 
be referred to 12-M-0063 only if they allow sharing the data and PHI. 
 
[11C]PBR28 PET scan: 
 
The NIH Clinical Center PET Dept. Radiochemistry Laboratory will synthesize and 
perform quality control for [11C]PBR28. [11C]PBR28, which is for research use only, will be 
used under IND #127,685 (sponsor:  NIH Clinical Center). In women, a pregnancy test will be 
conducted not more than 24 hours before the PET scan and must be negative. Participants will be 
asked not to take alcohol drink or a drug of abuse within 24 hours of the PET scan. 
 
One antecubital venous and one radial arterial catheter will be placed. The venous 
catheter is for radioligand injection and the arterial catheter is for blood sampling. An 
anesthesiologist or credentialed staff in the Vascular Access Department will place the arterial 
catheter in the subject’s wrist after numbing the area with a local anesthetic to minimize 
discomfort.  
 
The subject will then undergo scanning in a PET, PET/CT, or PET/MRI camera located 
at the Clinical Center of NIH. The subject will be placed on the scanner bed with his/her head 
held firmly in place with a thermoplastic mask fixed to the bed. An initial transmission scan for 
PET, or a pre-emission CT for PET/CT camera will provide a measured attenuation correction. 
The PET/MRI camera does not require a transmission scan using radioactivity because 
attenuation is measured by an MRI scan. The radioligand (~10 - 20 mCi of [11C]PBR28) will be 
injected intravenously. The maximum allowed mass of the radiotracer will be 10 μg per 
injection. The scan will last approximately 2 - 2.5 hours with an additional ~ 2 - 2.5 hours for 
preparations such as catheter insertion. 
 
To measure input function of the radioligand, blood samples will be obtained manually 
from the arterial line. The total blood sampling volume during the scan will be no more than 100 
mL. 
 
Pulse, blood pressure, and respiratory rate will be recorded within 3 h before tracer 
injection, and again at about 15, 30, 90, and 120 min after tracer injection. Before discharge, the 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 15 of 48 
arterial and venous catheters will be removed and catheter sites will be assessed for any evidence 
of vascular changes or trauma prior to releasing the subject from the NIH. Participants will be 
monitored during the PET procedure for the development of excessive anxiety and any adverse 
effect. 
 
If the PET scan is cancelled or incomplete due to synthesis failure of [11C]PBR28 or to 
camera problems and the subject did not receive any radioactive material, the scan will be 
repeated on the same or on another day. The transmission scan may be repeated as well. 
 
MRI scan: 
 
TBI subjects will have MRI scans either under protocol 10-N-N122 or the current 
protocol. Healthy subjects will have a brain MRI scan under the current protocol. If healthy 
subjects had a high resolution structural MRI scan within one year, an MRI scan may not be 
obtained under the current protocol. Under the current protocol, MRI scans will be performed at 
the Clinical Center of the NIH. Subjects will be screened for MRI safety using the screening 
questionnaire used by the Radiology and Imaging Sciences Program of the Clinical Center 
(Appendix 3). Subjects will be informed that while in the scanner they will hear loud knocking 
noises, and they will be fitted with earplugs or earmuffs to muffle the sound. Subjects will be 
able to communicate with the MRI staff at all times during the MRI scan, and they may ask to be 
moved out of the machine at any time. 
 
TBI subjects who qualify to receive gadolinium contrast will receive the contrast agent 
through an IV catheter. A needle will be used to guide the catheter into one of the subject’s arms. 
The needle will be removed, leaving only the catheter in the vein. The catheter will be taped to 
the skin to hold it in place. Healthy subjects will not receive gadolinium contrast. For TBI 
subjects GFR will be estimated using standard methods from creatinine clearance rate obtained 
as part of the clinical laboratory work-up Subjects with a GFR < 60 mL/min will be excluded 
from receiving gadolinium contrast agent and will receive an MRI without contrast only. 
 
It is not known if MRI is completely safe for a developing fetus. Therefore, all women of 
childbearing potential will have a pregnancy test performed no more than 24 hours before each 
MRI scan.  
 
One MRI session will last approximately one hour. MRI scan sequences for TBI subjects 
may consist of commercially available sequences including but not limited to: diffusion weighted 
imaging (DWI) or diffusion tensor imaging (DTI), dynamic susceptibility contrast and or arterial 
spin labeling perfusion weighted imaging (PWI), gradient recalled echo (GRE) and/or T2* 
susceptibility weighted imaging (SWI), T2 weighted fluid attenuated inversion recovery (T2-
FLAIR), high resolution anatomical image (3DT1-SPGR), post-contrast FLAIR and T1. MRI 
scan sequences for healthy subjects include a high resolution anatomical sequence to coregister 
to PET images and may also include T2-weighted, and FLAIR images. If the image quality of a 
given sequence is inadequate (eg, due to subject motion) these may be repeated at the discretion 
of the MRI technologist or radiologist. 
 
Neuropsychology tests and TBI assessment batteries: 
 
TBI subjects will take the following neuropsychological tests. The addition of 
neuropsychological testing to the protocol will provide data from standardized measures of 
cognitive functioning to compare with imaging data regarding inflammation.  The 
Neuropsychological data not only allows for a functional measure of the effects of 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 16 of 48 
neuroinflammation, but also allows for an object measure of the subjects level of cognitive 
impairment.  
The test listed below will be administered by a trained psychometrist under the 
supervision of a neuropsychologist.  Testing is conducted face to face in a standard setting using 
standardized administration procedures.  Total testing time for visits one (< ~ 10 days), three (~ 3 
months), and a later time point between ~5 months and 5 years is approximately 80 minutes and 
approximately 50 minutes on visit two (second visit < ~ 10 days).  Some of the tests have 
multiple forms which allow for administration of tests in close temporal proximity.  To avoid 
practice effects tests without alternate forms will only be administered at time point one and 
three. 
These are standardized neuropsychological tests which are well validated for use with this 
population.  There are no known physical risks to the use of these tests.  Subjects may experience 
frustration and/or fatigue from participation in neuropsychological testing.  Subjects are 
monitored throughout testing and should fatigue or frustration interfere with testing, rest time 
will be give or the testing will be discontinued to avoid excessive distress to the subject. 
• Delis-Kaplan Executive Function System (D-KEFS) Sorting Test (Free Sort 
Condition only): An executive functioning test of concept-formation, reasoning skills, 
and problem-solving abilities. The free sort conditions the examinee is asked to sort six 
mixed-up cards into two groups, three cards per group, according to as many different 
categorization rules or concepts as possible, and to describe the concepts used to generate 
each sort.  There are two equivalent forms of the test which will be administered in 
alternating order.  The Free Sort Condition of the D-KEFS Sorting Test takes 
approximately 5-10 minutes to administer. 
• Delis-Kaplan Executive Function System (D-KEFS) Verbal Fluency Test:  A 
language and executive functioning test from within D-KEFS with three conditions 
which evaluate spontaneous production of words beginning with a given letter, of a given 
class within a limited amount of time, and switching between words from different 
categories. There are two equivalent forms of the test which will be administered in 
alternating order.  The D-KEFS Verbal Fluency Test takes approximately 10 minutes to 
complete.   
• Hopkins Verbal Learning Test (HVLT-R): A brief assessment of verbal learning and 
memory (recognition and recall) for individuals 16 years and older. It is easy to 
administer and score and is well-tolerated even by significantly impaired individuals. Its 
use has been validated with brain-disordered populations (e.g., Alzheimer's disease, 
Huntington's disease, amnestic disorders). Six distinct forms of the HVLT-R are available 
and we will be using four (forms 1, 2, 4, and 6) different forms, as these four are the most 
reliable; using different forms eliminates practice effects on repeated administrations. 
Each form consists of a list of 12 nouns (targets) with four words drawn from each of 
three semantic categories. The semantic categories differ across the six forms, but the 
forms are very similar in their psychometric properties. The HVLT-R tasks include three 
learning trials, a delayed recall trial (20-25 minute delay), and a yes/no delayed 
recognition trial. This recognition trial consists of a randomized list that includes the 12 
target words and 12 non-target words, six of which are drawn from the same semantic 
categories as the targets. Raw scores are derived for Total Recall, Delayed Recall, 
Retention (% retained), and a Recognition Discrimination Index. The HVLT-R takes 
approximately 15 minutes to administer. 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 17 of 48 
• Trail Making Test (TMT) Parts A and B:  A test of visual attention and task switching 
that requires visual scanning, number and letter sequencing, and visual motor speed.  The 
test requires the individual to connect the dots of 25 consecutive targets (numbers only in 
Trail A and then numbers and letters in Trail B) on a sheet of paper. The TMT take 
approximately 5-10 minutes to administer.  (will only be administered at time points one 
and three) 
• Wechsler Adult Intelligence Scale – Fourth Edition (WAIS-IV):  Digit span, Coding , 
Symbol Search and Arithmetic Subtests.  These subtests comprise the working memory 
and processing speed indices.  These subtests take approximately 15-20 minutes to 
administer.  This will be administered only at time point one. 
• Glasgow Outcome Scale-extended (GOS-E) 10 min 
The Glasgow Outcome Scale-extended (GOS-E) is an assessment of general functioning. 
This scale evaluates 8 categories: Dead, Vegetative State, Lower Severe Disability, 
Upper Severe Disability, Lower Moderate Disability, Upper Moderate Disability, Lower 
Good Recovery, and Upper Good Recovery. It takes approximately 10 minutes to 
administer by staff observation. 
• Brief Symptom Inventory (BSI) 10 min 
The BSI is used to identify self-reported clinically-relevant psychological symptoms in 
adolescents and adults. The shortened form of the BSI instrument provides a highly 
sensitive assessment of psychological factors. The BSI takes approximately 10 minutes to 
administer by interview.  
• Satisfaction with Life Scale (SWLS): 1 min 
The Satisfaction with Life Scale (SWLS) is a short 5-item instrument designed to 
measure global cognitive judgments of satisfaction with one's life. The scale is done by 
interview and usually requires only about one minute of a respondent's time to complete. 
 
 
Because the primary goal of this exploratory study is to assess the utility of PET TSPO 
imaging by comparing PET and MRI findings, we will not terminate the study even if TBI 
subjects miss component(s) of these neuropsychology tests. For non-English speakers, these 
neuropsychology tests will not be performed because non-English versions may not be available 
and tests through an interpreter may not be valid. Not doing the neuropsychology tests is 
acceptable because the primary goal of this exploratory study is to assess the utility of PET 
TSPO imaging. Some of the tests may be done under protocol 10-CC-0118 at ~ 3 months if the 
subject is also participating in 10-CC-0118. If the tests are done within one week under 10-CC-
0118, those results will be used and the tests will not be repeated for 12-M-0063. Healthy 
controls will not have these neuropsychological tests. 
 
Binding assays on blood cells and mRNA and cDNA assays to study TSPO 
To determine the affinity status of TSPO, binding assays using TSPO ligands and genetic 
assays on single nucleotide polymorphism will be performed. 
For these assays, approximately 60 mL venous blood will be drawn from healthy 
volunteers at the time of enrollment and also from all TBI subjects. Mononuclear cells will be 
separated and binding assays will be performed using [3H]PBR28 or [3H]PK 11195 with 
nonradiolabeled PK11195 and/or PBR28. Platelets may also be used for the binding assays. We 
may also examine the mRNA expression of TSPO by RT-PCR and Northern blotting and the 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 18 of 48 
polymorphisms of TSPO by cDNA sequencing. Blood samples may be stored for future genetic 
studies on binding affinity to TSPO if the subject agrees. The binding assays will be performed 
by Molecular Imaging Branch, and the genetic assays will be performed by Dr. McMahon’s lab 
of NIMH. 
 
HIV testing 
 
Because HIV infection was reported to increase TSPO (Cosenza-Nashat et al., 2009), it 
may affect the PET results. To obtain the information that may help interpreting the PET results, 
HIV testing will be performed for all participants. 
 
Because this study primarily focuses on local areas with MRI abnormalities as stated in 
section 11. Statistical analysis a. Analysis of data / study outcomes (page 23 of the protocol), it is 
unnecessary to exclude subjects with HIV infection and unnecessary to know the results of the 
HIV test before the PET scan(s). 
 
vi. 
Follow-up/termination procedures 
 
For TBI subjects, participation in this study will end after the last [11C]PBR28 PET scan. 
For healthy controls, participation in this study will end upon completion of a [11C]PBR28 PET 
and an MRI scan. 
 
TBI subjects enrolled in this research study will be under the medical supervision of 
Medical Advisory Investigator, Robert B. Innis, MD, PhD, during the study procedures at NIH. 
 
Research findings obtained under the current protocol, such as the results of [11C]PBR28 
PET scans and laboratory tests, will not be shared with participants or health care providers 
unless the finding requires further evaluation and care. We are not able to provide care to 
subjects for any relevant findings observed under this research study and, if needed, we will refer 
subjects to their healthcare provider. 
b. Relationship of this study to other protocols 
 
To test the sensitivity of [11C]PBR28 to detect neuroinflammation, for Group 1 
acute/subacute phase, we will study subjects who have shown abnormal MRI findings under 
protocol 10-N-N122 or in the CNRM Image Processing Core for the participants of the CNRM 
Recruitment Core protocol 11-N-0084 and other CNRM protocols. Therefore, subjects will be 
recruited from the participants of 10-N-N122, 11-N-0084, or other CNRM protocols. For Group 
2 chronic phase, we recruit TBI subjects who had injury ~5 months to 5 years ago and meet at 
least one of the criteria of Probable or Definite TBI. We recruit group 2 subjects from CNRM 
Recruitment Core and other CNRM protocols. 
 
The current protocol is related to the Center for Neuroscience and Regenerative Medicine 
(CNRM). CNRM is a collaborative intramural federal program involving the United States (US) 
Department of Defense (DoD) and the National Institutes of Health (NIH). It joins clinicians and 
scientists across disciplines to catalyze innovative approaches to traumatic brain injury (TBI) 
research. The Uniformed Services University of Health Sciences (USU) heads the operation of 
the CNRM (www.usuhs.mil/cnrm). 
 
The subjects participating in the current protocol may be referred to another CNRM-
related protocol (Leighton Chan, PI) of NIH Protocol 10-CC-0118 “Long Term Clinical 
Correlates of TBI: Imaging, Biomarkers, and Clinical Phenotyping Parameters”, for potential 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 19 of 48 
study eligibility and participation. Subjects will be informed in the written consent form that if 
they choose to participate in NIH Protocol 10-CC-0118, identifiable data in PHI will be shared. 
If the subjects participate in 10-CC-0118, they will be initially contacted by a study member of 
this PET protocol. 
 
Data will be shared with USU Protocol No. CNRM-004 “Biorepository and Informatics 
Warehousing” Brian M. Cox, PI, after all PHI has been removed and samples have been coded. 
c. Management of data and samples 
Storage 
All clinical imaging data will be transferred to the NIH Radiology and Imaging Sciences 
Picture Archiving and Communication System (PACS) for clinical interpretation of the MRI 
scans.  This system is password protected and access is limited to authorized NIH users. 
In addition, all imaging data will be transferred to a secure research server, associated 
with a study ID, and de-identified.  De-identified images will be stored and maintained by the 
CNRM.  The Director and PI of the CNRM Informatics Core, the Director and PI of CNRM 
Image Processing Core, and database administrative staff shall be granted the access required to 
perform data entry into the system as well as other typical database maintenance tasks. 
Blood samples will be assigned a code at the time of blood draws and a courier service 
will be used to transit the samples for processing and storage according to the CNRM-004 
protocol and related manual of operations (appendix 6). NIH will assign a Global Unique 
Identifier (GUID) to all samples and data submitted to the CNRM repository. The purpose of the 
GUID is to allow data and samples on the same subject, from multiple protocols and from 
different institutions, to be identified as coming from a single individual and to be combined in 
the repository.  PII will be entered on a local server and a one-way encryption using a keyed-
hash algorithm will be used to assign the GUID.  CNRM will not receive PII.  The one-way 
encryption assures that the GUID cannot be used to back-generate PII. 
Blood samples for in vitro binding assays and genetic assays on TSPO will be stored in 
secured freezers on the NIH campus and will not be discarded until fully utilized. Any loss or 
destruction of samples will be reported to the IRB. 
 
Data (including genomic data) and sample sharing plan 
This protocol is not subject to the Genomic Data Sharing (GDS) policy.   
 
Samples and data will be shared with the Center for Neuroscience and Regenerative Medicine 
(CNRM). Samples that have been delinked may then be sent to other non-CNRM repositories. 
Possible future research includes performing additional TSPO binding and genetic assays. 
Subject name and identifying information will be removed and replaced with a unique patient 
identifier. The key to the code will be kept in a separate, secure area. 
 
Data and samples may also be shared with collaborating laboratories at NIH or outside of NIH 
and/or submitted to NIH-designated repositories and databases if consent for sharing was 
obtained.  Repositories receiving data and/or samples from this protocol may be open-access or 
restricted access.  
 
Samples and data will be stripped of identifiers and may be coded (“de-identified”) or unlinked 
from an identifying code (“anonymized”). When coded data is shared, the key to the code will 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 20 of 48 
not be provided to collaborators, but will remain at NIH.  Data and samples may be shared with 
investigators and institutions with an FWA or operating under the Declaration of Helsinki (DoH) 
and reported at the time of continuing review.  Sharing with investigators without an FWA or not 
operating under the DoH will be submitted for prospective IRB approval.  Submissions to NIH-
sponsored or supported databases and repositories will be reported at the time of Continuing 
Review.  Submission to non-NIH sponsored or supported databases and repositories will be 
submitted for prospective IRB approval. 
 
Required approvals from the collaborating institution will be obtained and materials will be 
shipped in accordance with NIH and federal regulations.    
 
Re-consent will be obtained prior to sharing from participants whose data and samples were 
collected prior to the implementation of Amendment R, if consent was not previously obtained.  
 
Data sharing will be governed by standard data transfer agreements and approved by the 
CNRM and NIH ethics committees.  Data used outside of NIH as part of collaborations will be 
anonymized, although non-identifying demographic data (e.g., height, age, race) may be 
provided.  Participants will be informed of the possibility of data sharing during the informed 
consent process. 
 
8. Risks/ discomforts 
Risks of study participation and minimization of risks 
Potential risks and discomforts from this study include those associated with: i) medical 
examinations including laboratory testing, ii) radiation exposure risks, iii) PET scanning, iv) 
placement of arterial and venous lines, v) blood sampling, vi) MRI, and vii) cognitive testing. 
 
i) Medical Examination and Laboratory Testing 
 
No medical risks are associated with taking of medical history, physical examination, or 
laboratory tests other than risks from phlebotomy. Phlebotomy may lead to the formation of 
small subcutaneous hematomas caused by blood leaking from a punctured blood vessel. These 
hematomas typically cause only minor discomfort. There is also a small risk of infection at the 
site of the needle puncture, which can be readily treated with antibiotic therapy.  
 
ii) Radiation Exposure Risks 
Radiation exposure in this protocol will be from up to four [11C]PBR28 scans and four 
transmission scans for TBI subjects and one [11C]PBR28 and one transmission scan for healthy 
controls. The radiation absorbed dose for the transmission scans will depend on the scanner used. 
The effective dose of one transmission scan from a PET camera using a 68Ge source is 0.01 rem; 
for cameras using a 137Cs source, the dose is 0.0003 rem. The effective dose of one transmission 
scan for head from a PET/CT camera that uses CT for transmission is 0.6 rem. Based on data 
obtained from whole body imaging of healthy humans performed at the Molecular Imaging 
Branch (MIB) (Brown et al., 2007), we estimate that the highest effective dose calculated for 
humans from the current study who have three [11C]PBR28 scans using PET-CT is 1.65 rem 
within one year, which is well below NIH RSC annual guidelines of 5 rem. Some TBI subjects 
have one or two [11C]PBR28 scans within one year and will have lower levels of radiation 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 21 of 48 
exposure. Radiation Safety Committee requires us to report radiation exposure within a year, and 
no TBI subject will have four PET scans within one year. 
All subjects will be asked about any prior research participation involving radiation 
exposure so that the total exposure, in combination with the present study, does not exceed an 
effective dose of 5 rem per 12 months. 
 
iii) PET Scanning 
PET scanning presents no medical risk beyond that of the radioactivity exposure and 
risks of arterial line and intravenous line placement. Subjects with back problems may be 
uncomfortable lying flat for the scan. Subjects can communicate with trained health 
professionals while in the scanner and can stop the scan and withdraw from the study at any time 
if they wish to do so. 
Occasionally subjects become anxious during the scan. In that case, subjects can request 
the operator of the PET to stop the scan. 
 
iv) Arterial/Venous Line Placement 
Arterial catheterization has been shown to be a generally safe and reliable method of 
obtaining arterial blood samples (Lockwood, 1985). Placement of a radial arterial catheter may 
cause bruising or infection. There is also a risk of occlusion and microemboli. Over 5,000 arterial 
catheters have been placed at NIH and, of these, only two complications requiring a physician’s 
care were reported. In the first case, a small radial artery aneurysm developed several months 
later, which was successfully repaired surgically. In the second case, a radial artery thrombosis 
developed 28 days later, which was also successfully repaired surgically. The arterial line will be 
placed by a member of the anesthesiology staff or the Vascular Access Department after 
confirming normal double circulation (both radial and ulnar arteries). If there is a complication 
related to placement of an arterial catheter, medical care will be provided in accord with NIH 
policy. 
Intravenous catheters will be placed in subjects to minimize discomfort from phlebotomy. 
Venous catheter insertion, which is less invasive than arterial catheterization, can also be 
associated with bruising, infection, or clot formation. Using proper placement techniques will 
minimize these risks.  
 
v) Blood Sampling 
Subjects will have up to four [11C]PBR28 PET scans and healthy controls will have one 
[11C]PBR28 PET scan. Each scan will require no more than 125 mL for blood sampling. 
Careful screening of health status and CBC will be done at screening. Healthy controls 
may be screened under 01-M-0254 “The Evaluation of Patients with Mood and Anxiety 
Disorders and Healthy Volunteers.” Subjects will be asked not to donate blood for a period of 
eight weeks after participation is completed. The total blood drawn will be approximately 200 
mL for healthy controls and approximately 500 mL for TBI subjects who have four [11C]PBR28 
PET scans. These sampling volumes will not exceed 550 mL over any eight-week period, 
including blood drawn for clinical purposes. 
 
vi) MRI 
MRI is not associated with any known deleterious biological effects. MRI scanners of 1.5 
- 3.0 Tesla are widely used as clinical imaging tools. Subjects will be screened and excluded for 
the presence of any ferromagnetic metal in the body both at the time of recruitment and just prior 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 22 of 48 
to the MRI. Pregnancy testing will be done on women of childbearing potential before MRI 
scanning. The noise of the MRI scanner is loud and could damage hearing. Subjects will wear 
ear-plugs to minimize exposure to excessively loud noises. Subjects can also request that the 
operator stop the scan at any time. Because claustrophobic individuals find MRI scans difficult, 
subjects with this condition will be excluded at the time of recruitment. 
Gadolinium contrast will be administered to qualified TBI subjects. Symptoms from the 
contrast infusion are usually mild and may include coldness in the arm during the injection, a 
metallic taste, headache, and nausea. In an extremely small number of subjects, more severe 
symptoms have been reported, including shortness of breath, wheezing, hives, and lowering of 
blood pressure. Subjects will not receive gadolinium-based contrast agents if they report having a 
previous allergic reaction to this agent. All subjects will be asked about such allergic reactions 
before a contrast agent is administered. Because individuals with kidney disease who receive 
gadolinium for contrast are at risk for a condition called “nephrogenic systemic fibrosis” (NSF), 
which has resulted in a very small number of deaths, such individuals are not eligible to have 
MRI with contrast under this protocol. 
 
vii) Cognitive testing 
The cognitive tests are not harmful, but may be frustrating or stressful to some subjects. 
We will ask subjects to try their best and inform subject that no one performs perfectly on these 
tasks. We will also inform subjects that they may refuse to answer any question or to stop a test 
at any time and for any reason 
 
vii) Genetic testing on TSPO 
The genetic testing on TSPO that will be done as part of this study is done for research 
purpose only. Because relationship between genotype of TSPO or affinity of ligands to TSPO 
and health or diseases has not been established, the genetic testing done in this protocol does not 
provide information on subject’s health. 
9. Subject monitoring 
For PET scans, the injection site will be monitored for any evidence of vascular changes 
or trauma at the completion of the study. Participants will be monitored during the PET 
procedure for the development of excessive anxiety. A study team clinician and a PET technician 
will be present during the entirety of the scan. 
For MRI scans, serum creatinine and GFR will be checked before gadolinium-DTPA is 
given. Study personnel will closely monitor allergic reactions to gadolinium. During the scans, 
subjects can be observed directly through a window between two rooms or via closed circuit 
television. In addition, audible communication between subjects and the scanning personnel will 
be possible via intercom. Subjects can be removed from the scanner immediately upon request or 
in case of medical necessity. An MRI technician will be present during the scans, and a clinician 
is available in Radiology. Study staff will monitor subjects during other study procedures. 
During study procedures, .in the event that a subject displays aggressive or combative 
behavior, testing will be aborted and the subject will be evaluated by Medical Advisory 
Investigator, Robert B. Innis, MD, PhD, or by one of clinically credentialed Associate 
Investigator. 
 
Criteria for individual subject withdrawal 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 23 of 48 
Participants will be withdrawn from the study if they: 
▪ request to be withdrawn from the study 
▪ are unable to complete study evaluations because of unforeseen circumstances 
▪ develop any condition for which, in the investigator’s opinion and following adequate 
safety review, it is in the participant’s best interest to be withdrawn from the study 
▪ Fail to comply with study requirements. 
▪ Any serious adverse event related to the research 
10. Outcome measures 
 
The primary outcome measure will be the binding levels of [11C]PBR28 measured as 
total distribution volume VT and VT normalized to plasma free fraction (fP), VT / fP using dynamic 
brain data and metabolite-corrected arterial input function. Secondary outcome measures will 
include neuropsychology test scores obtained by the tests described in section 7. Study Design 
and Mehtods. A. Study phases. V. Study procedures. Neuropsychology tests. VT and VT / fP in the 
areas of MRI abnormalities in TBI subjects will be compared to those in the areas without MRI 
abnormalities in the same subject and VT and VT / fP in healthy controls. In TBI subjects, 
relationship between VT or VT / fP and neuropsychology test scores will also be studied. 
 
11. Statistical analysis 
a. Analysis of data / study outcomes 
 
Data obtained from TBI subjects who have a [11C]PBR28 brain within approximately 10 
days of head injury and are identified as low-affinity binders will be excluded based on the fast 
decline of brain activity (Kreisl et al., 2010). Healthy controls identified as low affinity binders 
will be excluded before their [11C]PBR28 brain scan. 
Group 1 of TBI - Acute/subacute phase: 
 
The main analysis will be performed to study whether [11C]PBR28 PET shows changes 
in TSPO in areas where radiologist(s) report changes in MRI. 
[11C]PBR28 binding will be measured as VT and VT / fP using dynamic brain data and 
metabolite-corrected arterial input function. These distribution volumes will be calculated in 
each voxel using the Logan plot and may also be calculated by other commonly used methods 
such as compartmental modeling and spectral analyses. In addition, to calculate distribution 
volumes from less noisy data, volumes of interest may be placed in individual PET images of the 
dynamic data and distribution volumes may be calculated by commonly used methods of 
quantification such as compartmental modeling and the Logan plot. VT and VT / fP in the areas of 
abnormal MRI findings will be compared with those on the contralateral side of the same subject 
if the MRI is normal on the contralateral side. In addition, VT and VT / fP in the areas of abnormal 
MRI findings will be compared with those of healthy controls. 
 
In addition to studying [11C]PBR28 binding in the areas with abnormal MRI findings, VT 
and VT / fP of [11C]PBR28 of TBI subjects in areas with normal MRI findings will be compared 
to those of healthy controls. HIV infection and usage of drugs of abuse may be a confounding 
factor in this comparison because HIV infection was reported to increase TSPO (Cosenza-Nashat 
et al., 2009) and drugs of abuse may cause neuroinflammation (Yamamoto et al., 2010). 
Therefore, the results of HIV tests, urine drug screen, and history of using drugs of abuse may 
help interpretation of the PET results. 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 24 of 48 
Group 2 of TBI - Chronic phase: 
 
[11C]PBR28 binding measured as VT and VT / fP will be compared between the site of 
injury and the contralateral side if it showed no structural changes at the time of injury and at the 
time of PET. In addition, PBR28 binding in all brain areas will be compared with that in healthy 
controls because a recent study using the old ligand [11C]PK 11195 showed increase in TSPO in 
certain brain regions irrespective of the site of brain injury (Ramlackhansingh et al., 2011). As 
stated above for Group 1, the results of HIV tests, urine drug screen, and history of using drugs 
of abuse may help interpretation of the PET results. 
For both Groups 1 and 2: 
 
As an exploratory analysis, we will also study the relationship between VT and VT / fP of 
[11C]PBR28 in TBI subjects in conjunction with their neuropsychology test scores. 
 
In addition to the quantitative analysis based on VT and VT / fP values, [11C]PBR28 
parametric images may be visually evaluated by study investigator(s) blind to subject's diagnosis, 
in order to inform future use in clinical settings. As an exploratory analysis, correlation between 
[11C]PBR28 binding and neuropsychological test scores will be studied. 
 
b. Criteria for significance, power analysis, and accrual number request 
 
In this exploratory study to investigate the ability of [11C]PBR28 PET to detect increases 
in TSPO, the primary goal is to measure the magnitude and variance of putative increases in 
[11C]PBR28 binding in inflammatory areas in TBI subjects. Those data may be used to design 
future studies with a larger sample size. If [11C]PBR28 binding is indeed increased in TBI 
subjects, statistical significance will be tested by comparing binding on the contralateral side in 
the same subject if the contralateral side shows normal MRI results, and also by comparing 
binding in healthy controls. The association between [11C]PBR28 binding and clinical scores 
obtained from the neuropsychological test scores may also be used to design future studies with a 
larger sample size.  The statistical significance of regression in the current study will also be 
assessed. 
 
Because of the exploratory nature of the current protocol, we request a relatively small 
sample size of 20 in each group. After taking into account dropouts, we expect to perform at 
least one [11C]PBR28 PET scan in approximately 15 subjects in each group. A pilot study of this 
sample size is usually adequate for studying the utility of PET brain molecular imaging and 
calculating the necessary sample size of future studies. 
12. Human Subjects Protection 
a. Subject selection 
 
The racial and ethnic distribution of the subjects will reflect those of the clinical 
population affected by TBI and the participating hospital. No gender or ethnic/racial background 
preference or exclusion will apply to subject recruitment. We anticipate that approximately 60% 
of the subjects will be male. 
b. Justification for inclusion / exclusion of children 
 
Because the study involves radiation exposure, children will be excluded. 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 25 of 48 
c. Justification for inclusion of other vulnerable subjects 
 
Written informed consent will not be waived for this study. We will include TBI subjects 
who signed a consent form for protocols 10-N-N122, 11-N-0084 or other CNRM protocols for 
him/herself without requiring a legally-authorized representative. Pregnant or breast feeding 
women will be excluded because of the radiation exposure from [11C]PBR28.   
 
Procedures for consent are described in Section 15. 
d. Justification of sensitive procedures (use of placebo, medication withdrawal, provocative 
testing) 
 
None of these sensitive procedures apply to this protocol. 
e. Safeguards for vulnerable populations 
 
Only TBI subjects who signed consent forms for protocols 10-N-N122, 11-N-0084 or 
other CNRM protocols for him/herself without requiring a legally-authorized representative will 
be eligible for this study. In addition, as described in Section 15, the Decision Making Capacity 
(DMC) of all TBI subjects will be assessed by a Clinical Research Advocate (CRA) from the 
Human Subjects Protection Unit (HSPU) of the NIMH Office of the Clinical Director (OCD) to 
determine whether a subject can give his/her own consent. Within 24 hours prior to any MRI or 
PET scan, blood and urine specimens will be collected and pregnancy tests will be performed on 
women of childbearing potential. Subjects with positive pregnancy tests will not undergo MRI or 
PET scans and will be withdrawn from the study. 
 
All study procedures will be performed at NIH. Emergent medical problems will be 
managed by the NIH Rapid Response Team or the Code Blue Team. Participants will be 
evaluated and can be admitted to 7SWN Neurology Unit or 3SWS Intensive Care Unit, as 
needed. Relevant circumstances include, but are not limited to: 1) seizure; 2) severe post-
concussive syndrome, such as migraine refractory to standard medical treatment; 3) any other 
unforeseen complications requiring acute medical stabilization. Care will be provided until the 
subject is stable or until care can be transferred to the subject’s own health care providers. For 
medical problems or conditions that occur outside of the NIH Clinical Center, participants will 
need to seek care and treatment from their primary care physician or a local emergency room.  
f. Qualifications of investigators 
Principal Investigator 
Masahiro Fujita, MD, PhD: Staff Scientist, Molecular Imaging Branch, NIMH/NIH; Dr. Fujita 
will be the Principal Investigator (PI) for this study. He has more than 15 years of experience in 
conducting clinical research in human subjects including radioligand imaging studies. As 
Principal Investigator, his responsibilities will include, but are not limited to, study design and 
implementation, oversight of how the protocol is conducted, obtaining informed consent from 
subjects, data analysis and interpretation, and publication of study results. 
 
Lead Associate Investigator 
Lawrence Latour, PhD: Dr. Latour’s area of expertise is neuroimaging in the acute care clinical 
setting. Since joining the NIH in 2000, Dr. Latour has designed investigations into the causes, 
mechanisms, and treatments of ischemic stroke in human participants using MRI, and has been 
responsible for developing and optimizing hardware and software techniques that assist in the 
study of stroke participants. Dr. Latour is a Staff Scientist in the Stroke Diagnostics and 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 26 of 48 
Therapeutics Section/NINDS. Dr. Latour is authorized to obtain consent and will provide 
oversight for all aspects of participant recruitment and protocol implementation. 
 
Associate Investigators 
John Butman, MD, PhD: Dr. Butman’s area of expertise is neuroradiology. His active areas of 
research involve optimizing both MRI techniques and analysis methods to provide for rapid, 
accurate imaging in the clinical setting in a completely transparent, automated manner. Dr. 
Butman is a staff clinician in the Radiology and Imaging Sciences department of the NIHCC. Dr. 
Butman is authorized to obtain consent and he will supervise MRI data acquisition and 
processing. 
 
Leighton Chan, MD, MPH: Dr. Chan is a tenured senior investigator in the NIH’s intramural 
research program. He is also Chief of Rehabilitation Medicine at the NIH Clinical Center. Dr. 
Chan’s area of expertise is rehabilitation. He has extensive training in the assessment and 
treatment of TBI, and has directed many clinical trials. Dr. Chan is authorized to obtain consent 
and will provide oversight for all aspects of participant recruitment and protocol implementation. 
 
William Charles Kreisl, MD: Clinical Fellow, Molecular Imaging Branch, NIMH/NIH. Dr. 
Kreisl is a credentialed clinician at the NIH Clinical Center. His responsibilities will include 
recruiting and evaluating healthy subjects, obtaining informed subject consent, PET scanning, 
data analysis and interpretation, and publication of study results. 
 
M. Desiree Ferraris Araneta, C-RNP: Nurse Practitioner, Molecular Imaging Branch, 
NIMH/NIH. Ms. Araneta has been a nurse practitioner for seven years, and a nurse for 35 years. 
She is a credentialed clinician at the NIH Clinical Center with patient care credentials that 
include prescriptive authority from the NIH Clinical Center and knowledge of the research 
protocol under which the scans will be performed. As an Associate Investigator, she will 
participate in recruitment and evaluation of healthy subjects, obtain informed consent from 
prospective participants, and participate in PET scanning. 
 
Denise Rallis-Frutos, DNP: Molecular Imaging Branch, NIMH/NIH is a doctoral research 
nurse specialist who has been an Associate Investigator with the NIMH since 1996. For the past 
eight years, Ms. Rallis-Frutos was an Associate Investigator on Dr. Wayne Drevets’ protocols 
using PET and MRI procedures and scans. Her responsibilities will include recruitment and 
evaluation of subjects, obtaining informed consent, and covering PET and MRI procedures. 
 
L. Christine Turtzo, MD, PhD:  Dr. Turtzo is a board-certified neurologist with clinical 
credentialing at the NIH Clinical Center.  Her responsibilities will include recruiting and 
evaluating subjects, obtaining informed subject consent, data analysis and interpretation, and 
publication of study results. 
 
Adriana J. Pavletic, MD, MS: Dr. Pavletic is a board certified family physician who has 
provided clinical support for various NIMH protocols since 2002 as a consultant, associate 
investigator and medically responsible investigator. Her responsibilities will include medical 
screening of healthy and patient volunteers and obtaining informed consent. 
 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 27 of 48 
Peter Herscovitch, MD: Dr. Herscovitch is the Chief of PET Dept, Clinical Center. His 
expertise is PET imaging and in particular quantitative analysis of brain PET imaging. Dr. 
Herscovitch will supervise procedures of the PET scans and is authorized to obtain consent. 
 
John Dsurney, PhD ABPP:  Dr. Dsurney is a board certified clinical psychologist and 
fellowship trained Neuropsychologist.  His areas of expertise are in psychological and 
neuropsychological assessments. His research is focused on the development and validation of 
psychometric instruments. Dr. Dsurney has extensive clinical experience with Traumatic Brain 
Injury, dementia, and multiple sclerosis. Dr. Dsurney will provide oversight for 
neuropsychological assessments and overall protocol implementation. Dr. Dsurney will not 
obtain consent. 
 
Christian Shenouda, MD:  Dr. Shenouda is a study physician in the Rehabilitation Medicine 
Department.  Dr. Shenouda’s area of expertise is in brain injury rehabilitation.  He completed his 
residency training in rehabilitation medicine and fellowship in acquired brain injury medicine.  
Dr. Shenouda will perform clinical evaluations to provide medical clearance to participate in the 
study. Dr. Shenouda will not obtain consent. 
 
Martin Cota, BA, CCRC:   Martin Cota is an ACRP Certified Clinical Research Coordinator 
with the Henry M. Jackson Foundation who is experienced in the coordination of clinical 
research trials with five years experience consenting and enrolling subjects in clinical trials.  He 
will be responsible for oversight of the study for the clinical procedures particularly the 
recruitment.  He is authorized to obtain consent. 
 
Gene-Jack Wang, MD (LNI, IRP, NIAAA): Dr. Wang is a Board Certified Nuclear Medicine 
Physician with more than 20 years of experience using PET and MR imaging to study drug 
abuse, alcoholism, ADHD, obesity and eating disorders. He will assist in consenting subjects and 
with research/data analysis. 
 
Corinde E. Wiers, PhD (LNI, IRP, NIAAA): Dr. Wiers is a Visiting Postdoctoral Fellow 
Psychologist with more than five years of experience using functional and structural 
neuroimaging studies on cognition and addiction, including psychological screening, testing and 
neuroimaging of cocaine and alcohol-dependent patients, healthy adults and pediatric 
populations. She will assist in consenting subjects and with research/data analysis. 
 
Medical Advisory and Associate Investigator 
Robert B. Innis, MD, PhD: Chief, Molecular Imaging Branch, NIMH/NIH; Dr. Innis is a 
credentialed clinician at the NIH Clinical Center. He has conducted clinical research in human 
subjects for more than 20 years, including radioligand imaging studies. As the Medical Advisory 
and an Associate Investigator, his responsibilities will include, but are not limited to, study 
design and implementation, oversight of how the protocol is conducted, obtaining informed 
consent from subjects, data analysis and interpretation, and publication of study results. 
13. Benefits 
 
This study does not offer direct benefit to participants but is likely to eventually yield 
generalizable knowledge about the role of neuroinflammation in TBI. 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 28 of 48 
14. Summary / classification of risk 
 
This protocol is classified as a more than minimal risk study due to the radiation 
exposure, arterial line placement, and blood sampling associated with [11C]PBR28 PET scans. 
The risks of the protocol are reasonable in light of the anticipated benefit derived from a better 
understanding of neuroinflammation in TBI. 
15. Consent documents and process 
 
The consent forms contain all required elements. 
Subjects with TBI: 
 
TBI subjects must all provide written informed consent. Only subjects who signed the 
consent form of protocol 10-N-N122 (only those who participate in the current study within ~5 
months of brain injury), 11-N-0084 (all TBI subjects), or other CNRM protocols (all TBI 
subjects) for him/herself without requiring a legally-authorized representative will be enrolled. In 
addition, DMC of all TBI subjects will be assessed by a Clinical Research Advocate (CRA) from 
Human Subject Protection Unit (HSPU) of the NIMH OCD to determine if a subject can give 
his/her own consent. HSPU will develop and administer the protocol-specific capacity 
assessment tool and document the outcome in the medical record. If a subject is determined to 
have Decision Making Capacity (DMC), consent may be obtained from the subject by the PI/AI. 
If clinical status changes between capacity assessment and consenting or PET, a clinically 
credentialed study investigator will judge if another capacity assessment is necessary. 
 
Subjects determined by the PI, his/her designee, or the HSPU not to have DMC will be 
excluded from this protocol. 
 
Consent monitoring may be provided by the HSPU on an as-needed basis. 
 
If a non-English speaking participant is unexpectedly eligible for enrollment, the 
participant will be provided with the CC Short Written Consent Form for Non-English Speaking 
Research Subjects in the participant’s native language and a verbal explanation of the purpose, 
procedures and risks of the study. The IRB-approved English consent form will serve as basis for 
the verbal explanation of the study. The investigator will obtain an interpreter unless the 
investigator is fluent in the prospective participant’s language. Preferably, the interpreter will be 
someone who is independent of the participant (i.e., not a family member). Interpreters provided 
by the CC will be used whenever possible. The interpreters will translate the IRB-approved 
English consent form verbatim and facilitate discussion between the participant and 
investigator.  An interpreter will be used throughout the subjects’ visit beginning with the 
consent form process and all procedures that can validly be done through an interpreter. 
The IRB-approved English consent form will be signed by the investigator obtaining 
consent and a witness to the oral presentation. The CC Short Written Consent Form will be 
signed by the participant and a witness who observed the presentation of information. The 
interpreter may sign the consent document as the witness and, in this case, will note “Interpreter” 
under the signature line. A copy of both signed forms will be provided to the participant to take 
home. 
The investigator obtaining consent will document the consent process in the participant’s 
medical record, including the name of the interpreter.  Further, all instances of use of the CC 
Short Written Consent Form will be reported to the IRB at the time of annual review. If the CC 
Short Written Consent Form is used three times or more for the same language within an IRB 
approval period, this will be reported to the IRB immediately.  


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 29 of 48 
 
Healthy Volunteers: 
 
HSPU will not be involved in obtaining informed consent from healthy volunteers. 
Healthy volunteers must all provide written informed consent.  
 
Details on Obtaining Informed Consent: 
 
For all healthy volunteers and TBI subjects, an investigator from the study will obtain 
informed consent by providing a detailed account that includes: 1) the rationale for the study; 2) 
the subject’s right to withdraw from the study at any time; 3) the need to keep their scheduled 
appointments and comply with the protocol; and 4) information regarding how noncompliance 
with the protocol can result in termination from the study. Informed consent will be obtained 
after the participant has demonstrated a thorough knowledge of the protocol. Consent will be 
obtained by the Principal Investigator or one of the Associate Investigators. 
 
Each subject will receive an oral and written explanation of the purposes and potential 
risks of participation in this protocol. Specifically, they will be told that (a) the information 
derived may eventually lead to better understanding of the role of neuroinflammation in TBI, (b) 
PET imaging as used in this study is a research tool, hence no diagnostic interpretation will be 
given, and (c) subjects will be given ample opportunity to ask questions of the investigators. If 
laboratory tests or medical examination show significant abnormalities, appropriate referrals will 
be made to address health problems.   
 
Consent for sharing of previously collected data and samples 
If consent was not obtained for broad sharing of data and samples under the original consent, 
written consent will be obtained via mail and telephone contact. A letter (see appendix 7) will be 
mailed/e-mailed to them along with two copies of the consent.  The letter will be followed by a 
phone call to assess interest.  If the participant is interested, a time will be arranged when a 
witness can be present on their end to go over the consent and answer questions. The potential 
participant will be instructed to sign and date one copy of the consent and have the witness also 
sign and date. The signed consent will be e-mailed or mailed back to the investigators in a 
prepaid envelope, and the participant will keep the other copy. The investigator who participated 
in the consent process will then sign the consent and a copy with all three signatures will be sent 
to the participant. 
 
16. Data and Safety monitoring 
a. Data and safety monitor  
Carlos Zarate, MD will serve as an independent data and safety monitor.  
 
b. Data and safety monitoring plan 
The PI will prepare a report on data and safety parameters for the Independent Monitor 
quarterly.  The Independent monitor will provide a written monitoring report to be submitted to 
the IRB at the time of continuing review.  
 
c. Criteria for stopping the study or suspending enrollment or procedures 
The PI will notify him within one week of any serious adverse event. The study will be 
stopped if there are any serious adverse event directly related to the study procedure until a 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 30 of 48 
determination can be made on whether to proceed with the study. In such cases, Dr. Zarate may 
consult with the investigators and IRB to determine if changes are needed for research to 
continue or if it will be closed. 
17. Quality Assurance 
a. Quality assurance monitor 
Quality assurance will be monitored by the PI, the research team and the Intramural 
Research Auditing Committee (IRPAC) serving NIAAA, NIDA and NIMH. 
b. Quality assurance plan 
IRPAC monitors intramural research studies to ensure compliance with GCP, 
organizational policies and regulations.  Audit frequency is determined by the IRPAC SOP based 
on the study level of risk.  Results of IRPAC audits are provided to the PI, The Clinical Director 
and the CNS IRB. As an IND study, this protocol will be subject to GCP audits at study initiation 
and after the first enrolled subject.  Timing of subsequent review will be established by IRPAC 
but no less frequent than every other year.   
 
18. Reporting of Unanticipated problems, adverse events and protocol deviations  
The Principal Investigator is responsible for detecting, documenting, and reporting unanticipated 
problems, adverse events (AEs), including serious adverse events (SAEs), and deviations in accordance 
with NIH policy, IRB requirements, and federal regulations. Relatedness to the research of all serious 
adverse events will be determined by the PI in consultation with the CD. 
Serious unanticipated problems and serious protocol deviations will be reported to the IRB and 
CD as soon as possible and in writing on the Problem Report Form not more than 7 days after the PI first 
learns of the event.  Not serious unanticipated problems and not serious deviations will be reported to the 
IRB and CD as soon as possible and in writing on the Problem Report Form not more than 14 days after 
the PI first learns of the event.  
Deaths will be reported to the Clinical Director within 7 days after the PI first learns of the event.  
All adverse events, deviations, and unanticipated problems will be summarized and reported at 
the time of Continuing Review. 
[C-11]PBR28 is administered under IND # 127,685. The PI will immediately report SAEs related 
to this IND to the Sponsor, NIH Clinical Center , according to the requirements of 21 CFR 312.64(b) and 
as agreed upon with the sponsor. The PI will record nonserious AEs and report them to the Sponsor when 
the Sponsor submits an annual report to the FDA. 
19. Alternatives to participation or alternative therapies 
 
This study does not provide treatment and does not replace any therapy that subjects may 
receive as part of standard care for head injury or TBI from the ED/Trauma Team or from their 
own physician. Subjects will not be asked to forego any treatment to participate in this study. 
Subjects may choose not to participate in this research study. The alternative, therefore, is not to 
participate. 
20. Privacy 
All research activities will be conducted in as private a setting as possible. 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 31 of 48 
21. Confidentiality 
 
The entire MRI dataset of TBI subjects will be transferred to the research PACS of the 
CNRM Image Processing Core(at the NIH) once it is IRB approved. Data will be assigned a 
study ID with personally-identifying information removed. Imaging data will be stored using 
codes that we assign. Image data will be kept in password-protected computers. Only study 
investigators will have access to the identified data. Members of the CNRM, Uniformed Services 
University, Henry M Jackson Foundation, and the US Department of Defense will have access to 
the study data for auditing purposes. After removing personal identifiers and labeling with a code 
number, blood samples for binding and DNA analyses will be stored in locked freezers. The 
samples will be kept for future assays. 
22. Conflict of Interest 
 
NIH guidelines on conflict of interest have been distributed to all investigators. No NIH 
investigators have reported a conflict of interest. 
23. Technology Transfer 
 
No technology transfer is involved in this protocol. 
24. Research and Travel Compensation 
 
As shown in the tables below, both TBI subjects and healthy controls will be 
compensated for time and research-related inconveniences. Local transportation costs will be 
paid for any participant who must travel to participate. For subjects recruited from remote cities, 
we will offer transportation costs at the government rate, as well as costs related to overnight 
stays. The payments will follow the established NIH guidelines. Study subjects will be 
compensated at current volunteer participation rates: $20.00 / first hour; $10.00 / hour thereafter. 
The reimbursement is broken down as follows:  
 
 
 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 32 of 48 
Healthy controls 
 
Inconvenience 
Units 
Pay for 
inconvenience 
(1) 
Time 
(h) 
Pay for 
time (2) 
Total Pay 
(1 + 2) 
Visit 1 (Outpatient) 
 
 
 
 
 
Medical history, physical 
exams, blood tests including 
blood sampling for binding and 
genetic assays, and urinalysis 
2 
$20 
2 
$30 
$50 
 
 
 
 
 
 
Visit 2 to NIH (Outpatient) 
 
 
 
 
 
MRI 
6 
$60 
1 
$20 
$80 
 
 
 
 
 
 
Visit 3 (Outpatient) 
 
 
 
 
 
PET scanning 
15 
$150 
4 
$50 
$200 
Arterial catheter 
6 
$60 
 
 
$60 
Antecubital venous catheter 
3 
$30 
 
 
$30 
Pregnancy test 
1 
$10 
 
 
$10 
Movement restriction 
1 
$10 
 
 
$10 
 
 
 
 
 
 
Total 
 
 
 
 
$490-500 
 
 
 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 33 of 48 
TBI subjects 
 
Inconvenience 
Units 
Pay for 
inconvenience 
(1) 
Time 
(h) 
Pay for 
time (2) 
Total Pay 
(1 + 2) 
Visit for screening (Outpatient) 
 
 
 
 
 
Medical history, physical 
exams, blood tests and genetic 
assays, and urinalysis 
2 
$20 
2 
$30 
$50 
 
 
 
 
 
 
Blood sampling for screening of 
PBR28 binding 
8 
$80 
1 
$20 
$100 
 
 
 
 
 
 
Each Visit for a PET scan 
(Outpatient, up to three visits) 
 
 
 
 
 
PET scanning 
15 
$150 
4 
$50 
$200 
Arterial catheter 
6 
$60 
 
 
$60 
Antecubital venous catheter 
3 
$30 
 
 
$30 
Pregnancy test 
1 
$10 
 
 
$10 
Movement restriction 
1 
$10 
 
 
$10 
 
 
 
 
 
 
Each visit for an MRI scan if it is 
done under this protocol 
(Outpatient, up to three visits) 
 
 
 
 
 
MRI 
6 
$60 
1 
$20 
$80 
Total amount of the payment ranges from $430-440 for those who have one PET and one MRI 
scan within ~10 days of injury without having blood sampling for binding assay and to $1680-
1710 for those who have four PET and four MRI scans. 
 
 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 34 of 48 
25. References 
Brown, A.K., Fujita, M., Fujimura, Y., Liow, J.-S., Stabin, M., Ryu, Y.H., Imaizumi, M., Hong, 
J., Pike, V.W. & Innis, R.B. (2007) Radiation dosimetry and biodistribution in monkey 
and man of 11C-PBR28, a PET radioligand to image inflammation. J. Nucl. Med., 48, 
2072-2079. 
 
Cernak, I., O'Connor, C. & Vink, R. (2001) Activation of cyclo-oxygenase-2 contributes to 
motor and cognitive dysfunction following diffuse traumatic brain injury in rats. Clin Exp 
Pharmacol Physiol, 28, 922-925. 
 
Conzen, M., Ebel, H., Swart, E., Skreczek, W., Dette, M. & Oppel, F. (1992) Long-term 
neuropsychological outcome after severe head injury with good recovery, pp. 45-52. 
 
Cosenza-Nashat, M., Zhao, M.L., Suh, H.S., Morgan, J., Natividad, R., Morgello, S. & Lee, S.C. 
(2009) Expression of the translocator protein of 18 kDa by microglia, macrophages and 
astrocytes based on immunohistochemical localization in abnormal human brain. 
Neuropathol Appl Neurobiol, 35, 306-328. 
 
Folkersma, H., Boellaard, R., Yaqub, M., Kloet, R.W., Windhorst, A.D., Lammertsma, A.A., 
Vandertop, W.P. & van Berckel, B.N. (2011) Widespread and prolonged increase in (R)-
(11)C-PK11195 binding after traumatic brain injury. J Nucl Med, 52, 1235-1239. 
 
Fujita, M., Imaizumi, M., Zoghbi, S.S., Fujimura, Y., Farris, A.G., Suhara, T., Hong, J., Pike, 
V.W. & Innis, R.B. (2008) Kinetic analysis in healthy humans of a novel positron 
emission tomography radioligand to image the peripheral benzodiazepine receptor, a 
potential biomarker for inflammation. Neuroimage, 40, 43-52. 
 
Green, R.E., Colella, B., Hebert, D.A., Bayley, M., Kang, H.S., Till, C. & Monette, G. (2008) 
Prediction of Return to Productivity After Severe Traumatic Brain Injury: Investigations 
of Optimal Neuropsychological Tests and Timing of Assessment. Archives of physical 
medicine and rehabilitation, 89, S51-S60. 
 
Imaizumi, M., Briard, E., Zoghbi, S.S., Gourley, J.P., Hong, J., Fujimura, Y., Pike, V.W., Innis, 
R.B. & Fujita, M. (2008) Brain and whole-body imaging in nonhuman primates of 
[11C]PBR28, a promising PET radioligand for peripheral benzodiazepine receptors. 
Neuroimage, 39, 1289-1298. 
 
Imaizumi, M., Briard, E., Zoghbi, S.S., Gourley, J.P., Hong, J., Musachio, J.L., Gladding, R., 
Pike, V.W., Innis, R.B. & Fujita, M. (2007a) Kinetic evaluation in nonhuman primates of 
two new PET ligands for peripheral benzodiazepine receptors in brain. Synapse, 61, 595-
605. 
 
Imaizumi, M., Kim, H.-J., Zoghbi, S.S., Briard, E., Hong, J., Musachio, J.L., Ruetzler, C., 
Chuang, D.-M., Pike, V.W., Innis, R.B. & M., F. (2007b) PET imaging with [11C]PBR28 
can localize and quantify upregulated peripheral benzodiazepine receptors associated 
with cerebral ischemia in rat. Neurosci. Lett., 411, 200-205. 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 35 of 48 
 
Kreisl, W.C., Fujita, M., Fujimura, Y., Kimura, N., Jenko, K.J., Kannan, P., Hong, J., Morse, 
C.L., Zoghbi, S.S., Gladding, R.L., Jacobson, S., Oh, U., Pike, V.W. & Innis, R.B. (2010) 
Comparison of [11C]-(R)-PK 11195 and [11C]PBR28, two radioligands for translocator 
protein (18 kDa) in human and monkey: Implications for positron emission tomographic 
imaging of this inflammation biomarker. Neuroimage, 49, 2924-2932. 
 
Kreisl, W.C., Mbeo, G., Fujita, M., Zoghbi, S.S., Pike, V.W., Innis, R.B. & McArthur, J.C. 
(2009) Stroke incidentally identified using improved positron emission tomography for 
microglial activation. Arch Neurol, 66, 1288-1289. 
 
Langlois, J.A., Rutland-Brown, W. & Thomas, K.E. (2006) Traumatic Brain Injury in the United 
States: Emergency Department Visits, Hospitalizations, and Deaths. In Centers for 
Disease Control and Prevention, N.C.f.I.P., Control, a. (eds), Atlanta. 
 
Lloyd, E., Somera-Molina, K., Van Eldik, L.J., Watterson, D.M. & Wainwright, M.S. (2008) 
Suppression of acute proinflammatory cytokine and chemokine upregulation by post-
injury administration of a novel small molecule improves long-term neurologic outcome 
in a mouse model of traumatic brain injury. J Neuroinflammation, 5, 28. 
 
Lockwood, A.H. (1985) Invasiveness in studies of brain function by positron emission 
tomography (PET). J. Cereb. Blood Flow. Metab., 5, 487-489. 
 
Oh, U., Fujita, M., Ikonomidou, V.N., Evangelou, I.E., Matsuura, E., Harberts, E., Ohayon, J., 
Pike, V.W., Zhang, Y., Zoghbi, S.S., Innis, R.B. & Jacobson, S. Translocator Protein 
PET Imaging for Glial Activation in Multiple Sclerosis. J Neuroimmune Pharmacol, In 
press. 
 
Owen, D.R., Gunn, R.N., Rabiner, E.A., Bennacef, I., Fujita, M., Kreisl, W.C., Innis, R.B., Pike, 
V.W., Reynolds, R., Matthews, P.M. & Parker, C.A. (2011) Mixed-affinity binding in 
humans with 18-kDa translocator protein ligands. J Nucl Med, 52, 24-32. 
 
Owen, D.R., Howell, O.W., Tang, S.P., Wells, L.A., Bennacef, I., Bergstrom, M., Gunn, R.N., 
Rabiner, E.A., Wilkins, M.R., Reynolds, R., Matthews, P.M. & Parker, C.A. (2010) Two 
binding sites for [3H]PBR28 in human brain: implications for TSPO PET imaging of 
neuroinflammation. J Cereb Blood Flow Metab, 30, 1608-1618. 
 
Pierce, C.A. & Hanks, R.A. (2006) Life satisfaction after traumatic brain injury and the World 
Health Organization model of disability. Am J Phys Med Rehabil, 85, 889-898. 
 
Ramlackhansingh, A.F., Brooks, D.J., Greenwood, R.J., Bose, S.K., Turkheimer, F.E., 
Kinnunen, K.M., Gentleman, S., Heckemann, R.A., Gunanayagam, K., Gelosa, G. & 
Sharp, D.J. (2011) Inflammation after trauma: microglial activation and traumatic brain 
injury. Ann Neurol, 70, 374-383. 
 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 36 of 48 
Selassie, A.W., Zaloshnja, E., Langlois, J.A., Miller, T., Jones, P. & Steiner, C. (2008) Incidence 
of long-term disability following traumatic brain injury hospitalization, United States, 
2003. J Head Trauma Rehabil, 23, 123-131. 
 
Soustiel, J.F., Zaaroor, M., Vlodavsky, E., Veenman, L., Weizman, A. & Gavish, M. (2008) 
Neuroprotective effect of Ro5-4864 following brain injury. Exp Neurol, 214, 201-208. 
 
Wagner, A.K., Hammond, F.M., Sasser, H.C. & Wiercisiewski, D. (2002) Return to productive 
activity after traumatic brain injury: relationship with measures of disability, handicap, 
and community integration. Arch Phys Med Rehabil, 83, 107-114. 
 
Yamamoto, B.K., Moszczynska, A. & Gudelsky, G.A. (2010) Amphetamine toxicities: classical 
and emerging mechanisms. Annals of the New York Academy of Sciences, 1187, 101-121. 
 
Yu, I., Inaji, M., Maeda, J., Okauchi, T., Nariai, T., Ohno, K., Higuchi, M. & Suhara, T. (2010) 
Glial cell-mediated deterioration and repair of the nervous system after traumatic brain 
injury in a rat model as assessed by positron emission tomography. J Neurotrauma, 27, 
1463-1475. 
 
Zaloshnja, E., Miller, T., Langlois, J.A. & Selassie, A.W. (2008) Prevalence of long-term 
disability from traumatic brain injury in the civilian population of the United States, 
2005. J Head Trauma Rehabil, 23, 394-400. 
 
 
 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 37 of 48 
26. Appendices 
1. Eligibility checklist 
 
Eligibility Checklist for TBI participants Group 1 
CNRM 
Protocol Number: ______________                                                                                                                         Date: ___/____/___ 
Screen Number: ________________ Subject Number: _______________ 
Inclusion Criteria:  
All responses must be “YES” for a subject to be eligible. 
1. Diagnosis of non-penetrating TBI within ~ 5 months 
 
 Yes 
  No 
 
2. Ambulatory 
 Yes 
  No 
 
3. Able to provide self consent without a legally-authorized representative based on the assessment of the Decision 
Making Capacity (DMC) by Human Subjects Protection Unit (HSPU) 
 Yes 
  No 
 
Show abnormal MRI findings consistent with traumatic brain injury in protocol 10-N-N122 
or in an CNRM protocol 
 Yes 
  No 
 
5. Age 18 years or older 
 
 Yes 
  No 
 
 
 
 
PI or Designee Signature:  _____________________________________ 
 
Date:  ____/______/_______ 
 
 
 
Exclusion Criteria: 
All responses must be “No” for a subject to be eligible. 
1. Present or past history of brain disease other than TBI. 
 Yes 
  No 
 
2. Determined to have decreased decision-making capacity. 
 Yes 
  No 
 
3. Subjects that have abnormal findings on MRI obtained under protocol 10-N-N122 that are suggestive of a diagnosis
other than TBI. 
 Yes 
  No 
 
4. 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 determines 
the eligibility. 
 Yes 
  No 
 
5. Contraindication to MRI scanning including any non-organic implant 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 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 patient’s eyes). 
 Yes 
  No 
 
6. Conditions precluding entry into the scanner (e.g. morbid obesity, claustrophobia, etc.). 
 Yes 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 38 of 48 
  No 
 
7. Pregnant women or women who are breast-feeding. 
 
 Yes 
  No 
 
8. Exposure to research related radiation in the past year, which when combined with this study would be above the 
allowable limits. 
 Yes 
  No 
 
 
PI or Designee Signature:  _____________________________________ 
 
Date:  ____/______/_______ 
 
 
 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 39 of 48 
 
Eligibility Checklist for TBI participants Group 2 
CNRM 
Protocol Number: ______________                                                                                                                         Date: ___/____/___ 
Screen Number: ________________ Subject Number: _______________ 
Inclusion Criteria:  
All responses must be “YES” for a subject to be eligible. 
1. Head injury ~ 5 months – 5 years ago 
 
 Yes 
  No 
 
2. Enrolled in CNRM Recruitment Core protocol 11-N-0084 or another CNRM protocol 
 Yes 
  No 
 
3. Meet at least one of the criteria of Probable or Definite TBI established by CNRM 
 Yes 
  No 
 
4. Ambulatory 
 Yes 
  No 
 
5. Able to provide self consent without a legally-authorized representative based on the assessment of the Decision 
Making Capacity (DMC) by Human Subjects Protection Unit (HSPU) 
 Yes 
  No 
 
6. Age 18 years or older 
 
 Yes 
  No 
 
 
 
 
PI or Designee Signature:  _____________________________________ 
 
Date:  ____/______/_______ 
 
 
 
Exclusion Criteria: 
All responses must be “No” for a subject to be eligible. 
1. Present or past history of brain disease other than TBI. 
 Yes 
  No 
 
2. Determined to have decreased decision-making capacity. 
 Yes 
  No 
 
3. Subjects that have abnormal findings on MRI obtained under protocol 10-N-N122 that are suggestive of a diagnosis
other than TBI. 
 Yes 
  No 
 
4. 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 determines 
the eligibility. 
 Yes 
  No 
 
5. Contraindication to MRI scanning including any non-organic implant 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 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 patient’s eyes). 
 Yes 
  No 
 
6. Conditions precluding entry into the scanner (e.g. morbid obesity, claustrophobia, etc.). 
 Yes 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 40 of 48 
  No 
 
7. Pregnant women or women who are breast-feeding. 
 
 Yes 
  No 
 
8. Exposure to research related radiation in the past year, which when combined with this study would be above the 
allowable limits. 
 Yes 
  No 
 
 
PI or Designee Signature:  _____________________________________ 
 
Date:  ____/______/_______ 
 
 
 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 41 of 48 
 
Eligibility Checklist for healthy participants 
CNRM 
Protocol Number: ______________                                                                                                                         Date: ___/____/___ 
Screen Number: ________________ Subject Number: _______________ 
Inclusion Criteria:  
 
1. Healthy without past or present history of brain disease 
 
 Yes 
  No 
 
2. Age 18 years or older 
 
 Yes 
  No 
 
 
 
 
PI or Designee Signature:  _____________________________________ 
 
Date:  ____/______/_______ 
 
 
 
Exclusion Criteria: 
 
1. Any past or present Axis I disorder. The exception is substance abuse which ended over 6 months prior to enrollme
 Yes 
  No 
 
2. Contraindication to MRI scanning including any non-organic implant 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 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 patient’s eyes). 
 
 Yes 
  No 
 
3. Conditions precluding entry into the scanner (e.g. morbid obesity, claustrophobia, etc.). 
 
 
 Yes 
  No 
 
4. Pregnant women or women who are breast-feeding. 
 
 Yes 
  No 
 
5. Clinically significant laboratory abnormalities, as defined as laboratory values that are out of normal range or 
require clinical workup and/or treatment. 
 Yes 
  No 
 
6. Exposure to research related radiation in the past year, which when combined with this study would be above the 
allowable limits. 
 Yes 
  No 
7. Previously determined as a low-affinity binder in another study on TSPO 
 Yes 
  No 
8. Positive results of urine drug screen on enrollment. 
 Yes 
  No 
 
 
PI or Designee Signature:  _____________________________________ 
 
Date:  ____/______/_______ 
 
 
 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 42 of 48 
2. Brief explanation provided by investigators of protocol 10-N-N122 to TBI subjects as an 
advertisement 
Protocol # 12-M-0063 PET Imaging of Translocator Protein in Patients with Traumatic Brain 
Injury” 
 
Approved by NIMH CNS IRB on 12/30/2011 
 
Principal Investigator: Masahiro Fujita, MD, PhD, National Institute of Mental Health, National 
Institutes of Health 
 
Contact: Holly Giessen (301-435-8982) 
 
We are looking for people with head injury who are willing to participate in an imaging 
study. The study will be done at National Institutes of Health (NIH) in Bethesda, Maryland. 
 
The purpose of this research study is to measure a particular protein (called the translocator 
protein) in injured brain by using an imaging technique called positron emission tomography 
(PET) scanning. We would like to perform PET scanning because your MRI scan done under 
another protocol 10-N-N122 "Evaluation, Pathogenesis, and Outcome of Subjects with or 
Suspected Traumatic Brain Injury" showed some changes, which make us expect to find changes 
in PET. By doing PET scanning, we hope to better understand changes in brain after head injury. 
 
PET images are created by the use of small amounts of radioactive chemicals which are injected 
through a vein into the body. 
 
We will ask you to have one - three PET scans over about three months. Each PET scan takes 
about 2 hours to complete. By including time of the preparation for the PET scan, you will need 
to spend about 6 hours at NIH on the day of each PET scan. 
 
In addition to PET scans, we may ask you to do MRI scan(s) at NIH. 
 
You need to be older than 18 years to participate. 
 
We will pay you for your participation in the study. 
 
 
 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 43 of 48 
3. MRI safety screening questionnaire 
 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 44 of 48 
4. Biospecimin Repository Shipment Guidelines 
 
 
CNRM Shipping Requirements and Instructions 
 
 
Specimens being shipped to the CNRM Repository should be considered as Clinical/Diagnostic specimens and as 
such must be tripled packaged and compliant with IATA Packing Instructions 650.   See the 51st Edition (2010) IATA 
Regulations for complete documentation. 
 
Triple packaging consists of a primary receptacle(s), a secondary packaging and a rigid outer packaging. The primary 
receptacles must be packed in secondary packaging in such a way that, under normal conditions of transport, they 
cannot break, be punctured or leak their contents into the secondary packaging. Secondary packaging must be secured 
in outer packaging with suitable cushioning material. Any leakage of the contents must not compromise the integrity 
of the cushioning material or of the outer packaging. 
 
Packing and Labeling Guidelines for Clinical/Diagnostic Specimens: 
 
• 
The primary receptacle (blood draw tube or frozen vial) must be leakproof and must not contain more than 
1L. 
• 
The secondary packaging (biohazard bag) must be leakproof and if multiple blood tubes are placed in a single 
secondary packaging, they must be either individually wrapped or separated to prevent direct contact with 
adjacent blood tubes. 
• 
Absorbent material must be placed between the primary receptacle (blood tubes or the cryovial box 
containing the frozen vials) and the secondary packaging. The absorbent material should be of sufficient 
quantity in order to absorb the entire contents of the specimens being shipped. Examples of absorbent 
material are paper towels, absorbent pads, cotton balls or cellulose wadding. 
• 
A shipping manifest of specimens being shipped must be included between the secondary and outer 
packaging. 
• 
The outer shipping container must display the following labels: 
o 
Sender’s name and address 
o 
Recipient’s name and address 
o 
The words “Biological Substance, Category B” 
o 
UN3373   
 
o 
Class 9 label including UN 1845, and net 
weight if packaged with dry ice 
o 
Complete shipper example: 
 
 
 
Shipping Instructions for Blood Tubes: 
 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 45 of 48 
• 
Wrap tape around the stoppers of the various blood (yellow, lavender, red, Paxgene) tubes. 
• 
Place tubes in Styrofoam box for blood tubes, bubble wrap for blood tubes or individually wrapped or 
separated to prevent direct contact with adjacent blood tubes. 
• 
Place inside of biohazard bags with absorbent; ensure the biohazard bag is adequately sealed 
• 
Place the biohazard bag into a rigid outer package (shipping container) 
• 
Label shipping container with appropriate labels:  
o 
Sender’s name and address 
o 
Recipient’s name and address 
o 
The words “Biological Substance, Category B” 
o 
UN3373   
• 
If shipment is for local pickup and delivery contact Runners Inc. 301-948-7500 to schedule a pickup. Provide 
Runners Inc. with time and address location of pickup. Pickup time should no later than 2:00 pm if possible 
to allow for adequate time for processing at processing site. 
• 
A Bill of Lading will need to be filled out will sender and recipient information, as well as brief description 
of shipment content. FedEx shipments should be sent Monday thru Thursdays to avoid shipping delays or 
Friday. Specimen integrity can be vastly compromised if blood tubes are not processed 24 to 36 hours after 
collection. 
• 
Linda Brunson of the shipment via email and phone 
• 
Use FedEx Tracking to ensure the delivery is made 
Shipping Instructions for Frozen Specimens: 
 
• 
Place cryovials and Paxgen tube into a cryovial box (cryovial box and grids can be supplied by the CNRM 
Repository) 
• 
Place cryovial box with absorbent material inside biohazard bag; ensure the biohazard bag is adequately 
sealed 
• 
Place the biohazard bag into a rigid outer package (shipping container). The shipping container must also 
contain Styrofoam for the dry ice that must be placed in the shipper. The dry ice must surround and be place 
on top of the biohazard bag in order to ensure the frozen state of the specimens. 
• 
Label shipping container with appropriate labels:  
o 
Sender’s name and address 
o 
Recipient’s name and address 
o 
The words “Biological Substance, Category B” 
o 
UN3373   
• 
If shipment is for local pickup and delivery contact Runners Inc. 301-948-7500 to schedule a pickup. Provide 
Runners Inc. with time and address location of pickup. Pickup time should no later than 2:00 pm if possible 
to allow for adequate time for processing at processing site. 
• 
A Bill of Lading will need to be filled out with sender and recipient information, as well as brief description 
of shipment content. Specimens should be sent to the below address. If shipping from non local location use 
our preprinted FedEx forms. FedEx shipments should be sent Monday thru Wednesday to avoid shipping 
delays Thursday or Friday. FedEx does not replenish dry ice if shipments are delayed or held over during the 
weekend. 
 
 
Linda Brunson 
 
12725 Twinbrook Parkway Room 254B 
 
Rockville, MD 20852 
 
Phone: (301) 295-4612 
 
• 
Notify Linda Brunson of the shipment via email: Linda.Brunson.CTR@USUHS.mil 
• 
Use FedEx tracking to ensure the delivery is made 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 46 of 48 
5. Advertisement to Recruit Subjects with Traumatic Brain Injury 
 
 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 47 of 48 
6. TBI Evidence Form by CNRM 
 
 


CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 48 of 48 
 
7. Sample Letter for Consent for Data and Sample Sharing of Previously 
Collected Data and Samples 
 
DEPARTMENT OF HEALTH & HUMAN SERVICES                                                Public Health Service 
 
 
 
 
National Institutes of Health 
Building 10/Room B2L124  
Bethesda, Maryland 20892-1264 
Phone: 301-451-3021  
Protocol Number 12-M-0063 
[Date] 
 
Dear [Mr or Ms. Name] 
 
We are contacting you because you previously participated in a research study at 
NIMH: PET Imaging of Translocator Protein in Subjects with Traumatic Brain Injury, 
(study number 12-M-0063)   The study looked at whether a radioactive chemical 
[11C]PBR28, could be used to study changes in the brain of patients who have experience 
traumatic brain injury (TBI) 
 
We would like to get your permission to share your data and samples with other 
scientists, for future research projects, including those not related to brain changes 
in TBI.   Included with this letter are two copies of the consent form, which further 
explains the sharing.  Soon we will contact you by phone to see if you might be 
interested in allow us to share your data and samples.  If you are interested, a time 
will be arranged to explain the sharing, review the consent, and answer any 
questions you might have.   When we go over the consent, please have someone on 
your end of the phone to serve as a witness.  Once you agree to participate in 
sharing, you and the witness will sign and date the consent form. PLEASE DO NOT 
SIGN THE FORM UNTIL WE HAVE DISCUSSED IT WITH YOU.  You will then mail the 
consent form back to the investigator in the included pre-paid envelope.   You will 
keep the other copy.  Once we receive your signed consent, we will sign the form as 
well and mail you a copy with all three signatures. 
 
Sharing your data and samples is optional.  You are under no obligation to share 
your data and samples.    
 
If you have any questions, please contact Dr. Corinde Wiers at 301-451-3021. 
Thank you for your time, 
Masahiro Fujita, MD, PhD