The purpose of this study is to determine feasibility of noninvasive assessment of neuroinflammation in traumatic brain injury (TBI) with positron emission tomography (PET) using copper-64 chloride (64CuCl2) as a tracer (Cu-64 PET). TBI is a major cause of mortality and morbidity, particularly among persons below the age of 45. In pre- clinical animal models, therapies aimed at modulating excitatory neurotransmission, oxidative stress, and neurotrophic factors, among others, have been effective in limiting secondary neurodegeneration and improving neurological outcome. These interventions, however, have not proved effective in Phase III human clinical trials. There is a need for methods adequate for noninvasive assessment of TBI and selection of patients for treatment trials. Emerging evidence indicates that neuroinflammation plays an important role in the pathogenesis of TBI. PET is attractive for imaging neuroinflammation based on its high sensitivity and suitability for quantitative analysis. Although [11C] (R)-PK11195 is useful for PET of neuroinflammation in brain tissues, but the short-half life of C-11 radionuclide restrict its use to imaging centers with an onsite cyclotron. It is significant to search for additional tracers for imaging neuroinflammation with PET. It has been known that Inflammation is associated with increased uptake of copper by the inflammatory cells. We hypothesize that: 1) neuroinflammation in TBI is associated with increased uptake of copper, which may be assessed non-invasively with Cu-64 PET;2) Cu-64 PET may be used to select patients with active neuroinflammation for clinical trials of anti-inflammatory drugs;3) therapeutic effects of anti-inflammatory drugs on TBI may be monitored with Cu-64 PET, based on reduction of copper uptake in the brain tissues of TBI mice treated with anti-inflammation drugs. To test our hypothesis, we will conduct experimental PET of mice post Cortical Controlled Impact (CCI) to assess neuroinflammation in the traumatized brain tissues, using 64CuCl2 as a tracer.
The Specific aims of this proposed project are:
AIM 1 : To determine whether neuroinflammation in mice with TBI post can be assessed noninvasively and quantitatively with Cu-64 PET;
AIM 2 : To determine whether therapeutic effects of anti-inflammatory drugs on TBI can be monitored with Cu- 64 PET. We will use minocycline, a potent anti-inflammatory drug, in this proposed study. This new Cu-64 PET technology is expected to have significant impact on clinical management of the patients with TBI: 1) Cu-64 PET is expected to be useful for localization and quantitative assessment of neuroinflammation in the patients with TBI;2) Cu-64 PET is expected to be useful for selection of the TBI patients with active neuroinflammation for anti-inflammation drug clinical trials;3) Cu-64 PET is expected to be useful for monitoring anti-inflammatory therapies in patients with TBI.

Public Health Relevance

The purpose of this study is to determine feasibility of noninvasive assessment of neuroinflammation in traumatic brain injury (TBI) with positron emission tomography (PET) using copper-64 chloride (64CuCl2) as a tracer (Cu-64 PET). Cu-64 PET is expected to be useful for localization and quantitative assessment of neuroinflammation in the traumatized brain tissues, selection of patients with TBI for anti-inflammation drug trials, and monitoring therapeutic effects of anti-inflammatory drugs in patients with TBI.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS074394-02
Application #
8326063
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Hicks, Ramona R
Project Start
2011-09-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$208,295
Indirect Cost
$77,292
Name
University of Texas Sw Medical Center Dallas
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Peng, Fangyu; Muzik, Otto; Gatson, Joshua et al. (2015) Assessment of Traumatic Brain Injury by Increased 64Cu Uptake on 64CuCl2 PET/CT. J Nucl Med 56:1252-7
Peng, Fangyu (2014) Positron emission tomography for measurement of copper fluxes in live organisms. Ann N Y Acad Sci 1314:24-31