Cellular processes that have received much attention lately are those involved in TBI neuroinflammation. Microglial, astrocyte, and neuron cells resident in the central nervous system begin to react in the acute TBI phase and are subsequent and chronically activated. The role of activated microglia is to serve as the most important antigen-presenting cells and to synthesize inflammatory mediators and complement, which are crucial in the neuroinflammatory cascade after TBI. Microglia functions are very complex, since they have both neurotoxic and neuroprotective roles. Several researchers have suggested that the neuroinflammatory response may explain the great variability in long-term clinical course after TBI. Previous studies in TBI animal models have demonstrated that the inflammatory process may persist for at least a year, especially in the thalamus (Nagamoto-Combs et al. 2007, 2010). Human postmortem studies have also found microglia activation many years after TBI (Gentleman et al. 2004).

The neuroinflammatory response can be studied in vivo with PET using the radioligand ¹¹C-(R)-PK11195 (1-[2-chlorophenyl]-N-methyl-N-[1-methylpropyl]-3-isoquinoline carboxamide), which is a selective marker for activated microglia. (R)-PK11195 binds to the 18 kDa translocator protein (TSPO), expressed in the mitochondria of activated microglia. ¹¹C-(R)-PK11195 PET has previously been used to study neuroinflammation in several neurodegenerative diseases. Chen and Guilarte (2008) published an excellent overview of the use of TSPO as a biomarker for active neuroinflammation in experimental and human studies.

The first studies using ¹¹C-(R)-PK11195 PET in TBI patients have been published recently (Folkersma et al. 2011; Ramlackhansingh et al. 2011). In the paper by Folkersma and coworkers, a patient group in chronic stage with moderate or severe TBI (N = 8) and a control group (N = 7) were studied. ¹¹C-(R)-PK11195 PET and MRI images were acquired 6 months after TBI. ¹¹C-(R)-PK11195 BP_ND parametric images were generated. To generate a reference tissue input, the authors used supervised cluster analysis (Boellaard et al. 2008). Evaluation of the ¹¹C-(R)-PK11195 BP_ND was done in the whole brain and regionally. Group comparisons showed a significant increase of whole-brain ¹¹C-(R)-PK11195 BP_ND in the TBI group. This increase was not only observed in structurally affected brain regions (MRI) but also in apparently normal regions. On the other hand, there was no correlation between TBI severity (GCS) or neurological outcome (GOS) and whole-brain ¹¹C-(R)-PK11195 BP_ND. Although microglial activation is mostly a diffuse event in TBI, brain regions showing significant increases of ¹¹C-(R)-PK11195 BP_ND were the left and right frontal lobe, left and right thalamus, left parietal lobe, right temporal lobe, hippocampus and putamen, midbrain, and pons. An interesting finding was that ¹¹C-(R)-PK11195 BP_ND was maximal in the thalamus in six out of eight patients.

The study by Ramlackhansingh and coworkers (2011) investigated whether the inflammatory response persists in patients with chronic TBI and if this response was related to structural abnormalities and cognitive dysfunction. This paper included a group of patients with moderate to severe chronic TBI (N = 10). Five patients had focal damage visible in MRI images, while the other five did not show abnormalities. ¹¹C- (R)-PK11195 PET was performed on all patients at least 11 months after TBI. Like in the previous study, ¹¹C-(R)-PK11195 BP_ND parametric images were generated using supervised cluster analysis. Volumetric MRI and DTI were done to evaluate focal damage and the disruption of WM. Cognitive function was also evaluated. Group comparisons showed that ¹¹C-(R)-PK11195 BP_ND was increased in the thalami, putamen, occipital cortices, and posterior limb of the internal capsules in the patient group compared with controls (Fig. 45.3). Unlike the study by Folkersma and coworkers, they found no increase in ¹¹C-(R)-PK11195 BP_ND at the original site of focal brain injury, which is probably due to the different intervals which had elapsed after TBI in both studies. In the patient sample, a positive correlation was observed between ¹¹C-(R)-PK11195 BP_ND in the thalamus and the degree of cognitive impairment. ¹¹C-(R)-PK11195 BP_ND increase was not associated to structural damage found by volumetric MRI and DTI or the time elapsed after TBI. Like in the article by Folkersma, persistent microglia activation in chronic TBI patients was confirmed especially in subcortical regions. Taking into account the long intervals after injury in the patient sample, this paper also suggests that therapeutic interventions can be beneficial even for a long time after TBI.

Although longitudinal studies are required in larger patient samples, the results of both studies indicate that ¹¹C-(R)-PK11195 PET could become an attractive method for detecting secondary damage after TBI and could serve as guide for evaluating interventions directed toward manipulating the inflammatory cascade.

In recent years, there have been great efforts to develop other selective radioligands for neuroinflammation in order to overcome the limitations of ¹¹C-(R)-PK11195 (Chauveau et al. 2011; Antunes et al. 2012). Among these limitations are the high level of nonspecific binding; the low signal to noise ratio, which renders quantification difficult; and the fact that it is labeled with ¹¹C, which limits its use to medical institutions that have a cyclotron.

Perfusion SPECT using ^99mTc-hexamethyl-propyleneamine oxime (HMPAO) or ^99mTc-ethylene cysteine dimer (ECD) has been extensively used in TBI. Reviews of this neuroimaging modality have appeared regularly in the last years (Davalos and Bennett 2002; Cihangiroglu et al. 2002; Belanger et al. 2007; Tikofsky 2010; Tong et al. 2011). These reviews coincide in pointing out that perfusion SPECT has high negative predictive value during the acute phase in mild TBI. They also agree that perfusion SPECT, like ¹⁸F-FDG PET, is more sensitive than CT for identifying abnormalities in TBI during the first hours, detecting them in very early stages, when CT (or MRI) scans may still be negative. Abnormalities detected by perfusion SPECT are more extensive than those observed by structural neuroimaging. A recent study shows that the combination of structural neuroimages, such as CT, with perfusion SPECT using ^99mTc-ECD is useful to determine the extent and severity of TBI lesions and tissue viability in core, edema, and perilesional tissue (Pifarré et al. 2011). Figure 45.4 shows CT and SPECT perfusion imaging of a patient with left frontal primarily brain trauma.

Furthermore, using SPECT it is possible to study cell-specific processes related to TBI pathophysiology. Studies combining ¹²³I-2-β-carbomethoxy-3-β-(4-iodophenyl) tropane (β-CIT) and ¹²³I-iodobenzamide (IBZM) found nigrostriatal dysfunction in TBI patients, although the striatum was structurally relatively preserved, suggesting these studies may be useful in the evaluation of therapies directed toward reducing parkinsonian symptoms in TBI patients (Donnemiller et al. 2000). Another very recent animal study used N′,N′-diethyl-6-chloro-(4′-[¹²³I]iodophenyl)imidazo [1,2-a]pyridine-3-acetamide (¹²³I-CLINDE) for the in vivo monitoring of neuroinflammation by SPECT (Mattner et al 2011). ¹²³I-CLINDE is a highly specific radioligand for TSPO. A recent perfusion SPECT activation study investigated cognitive fatigue mechanisms in patients with mild TBI (Hattori et al. 2009). In this study, it was possible to show that there is frontocerebellar dissociation in patients with mild TBI that may explain cognitive impairment and cognitive fatigue in the chronic phase.

Technological advances in SPECT detector systems, hybrid SPECT–CT, continuous development of new gamma-emitting radioligands, and the application of modern methods of image analysis make the SPECT technique a valid alternative for the study of TBI, both for clinical practice and for research. Nevertheless, like ¹⁸F-FDG PET, evidence-based imaging studies are required to demonstrate its incremental validity in TBI. The main advantage of SPECT is that it is much less costly and is still more widely available on a worldwide scale in comparison to PET.