FDG-PET imaging in mild traumatic brain injury: a critical review

Abstract

Traumatic brain injury (TBI) affects an estimated 1.7 million people in the United States and is a contributing factor to one third of all injury related deaths annually. According to the CDC, approximately 75% of all reported TBIs are concussions or considered mild in form, although the number of unreported mild TBIs (mTBI) and patients not seeking medical attention is unknown. Currently, classification of mTBI or concussion is a clinical assessment since diagnostic imaging is typically inconclusive due to subtle, obscure, or absent changes in anatomical or physiological parameters measured using standard magnetic resonance (MR) or computed tomography (CT) imaging protocols. Molecular imaging techniques that examine functional processes within the brain, such as measurement of glucose uptake and metabolism using [(18)F]fluorodeoxyglucose and positron emission tomography (FDG-PET), have the ability to detect changes after mTBI. Recent technological improvements in the resolution of PET systems, the integration of PET with magnetic resonance imaging (MRI), and the availability of normal healthy human databases and commercial image analysis software contribute to the growing use of molecular imaging in basic science research and advances in clinical imaging. This review will discuss the technological considerations and limitations of FDG-PET, including differentiation between glucose uptake and glucose metabolism and the significance of these measurements. In addition, the current state of FDG-PET imaging in assessing mTBI in clinical and preclinical research will be considered. Finally, this review will provide insight into potential critical data elements and recommended standardization to improve the application of FDG-PET to mTBI research and clinical practice.

Keywords: FDG; clinical research; experimental research; fluorodeoxyglucose; mTBI; positron emission tomography; traumatic brain injury.

Figure 1

A two-compartment model that symbolizes FDG transport from blood plasma to tissue, as freely available FDG, with subsequent trapping in the cell by phosphorylation to FDG-6-PO₄. The compartment concentrations of FDG are represented by plasma (C^plasma), interstitial space (C^free), and cellular (C^cell). K₁ is the perfusion constant (ml of blood/g of tissue/min), and k₂, k₃, and k₄ are rate constants (min⁻¹) for diffusion back to blood plasma, phosphorylation of FDG, and de-phosphorylation, respectively. The arrow size represents the relative magnitude of the rate constants. The dashed vertical line indicates the blood-brain-barrier and the dashed arrow indicates the de-phosphorylation of FDG, which is typically insignificant (k₄ is 0 for the “irreversible” model).

Figure 2

T2-weighted MRI (TE = 60 ms) of a male SD rat brain with visible brain deformation 1 day post moderate CCI (left) and mild LFP (right) injury. Focal tissue damage and associated hyperintense edema is shown extending extracranially in both images.

Figure 3

FDG uptake, normalized to sham, at baseline (time 0), 3 and 24 h after a mild LFP showed less variability and greater depression when animals were anesthetized during uptake than when animals were awake during uptake. N = 3/group.

Figure 4

Standard FDG-PET images from three clinical TBI cases. (A) 25 y.o. male, single non-blast moderate TBI, imaged 5 months post-injury. No recorded medications or sleep difficulties, pain/headache, or vision problems. FDG-PET shows left temporal hypometabolism associated with mild volume loss/encephalomalacia on the CT. (B) 28 y.o. male, single non-blast severe TBI, imaged 12.5 months post-injury. No recorded medications or sleep difficulties, pain/headache, or vision problems. FDG-PET shows a more severe injury with prominent hypometabolism frontally (arrow) associated with encephalomalacia. (C) 35 y.o. male, history of repeat exposure to blast-related mTBI, imaged 43 months post-injury. Pain medication (ultram), mild body pain, and moderate sleep problems, no findings CT. FDG-PET shows prominent frontal hypermetabolism, which may be medication related. The color bar displayed in (C) applies to all images with red representing greater FDG uptake.

Figure 5

Representative diagram of FDG uptake as measured by PET imaging, normalized to reference region, based on animal modeling. The representative lines are drawn from data from our work on mTBI (Selwyn et al., 2013) and the work of others on moderate to severe TBI (Liu et al., ; Shultz et al., 2013).