Abstract
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Objectives Neuroinflammation is recognized as a secondary injury mechanism after traumatic brain injury (TBI) relevant to patient outcome. MRI can be used to identify foci of primary injury but not to differentiate a secondary inflammatory response. This study sought to investigate whether PET imaging of translocator protein (TSPO) detects neuroinflammation in TBI patients, which are not detectable by MRI, either around the primary site or in remote areas.
Methods Twenty five TBI subjects (49 ± 15 y.o., 5 females and 20 males) who showed TBI-related MRI changes were included in this PET study; 8 subjects within ~3 months of injury and 17 > ~3 months after injury. Glasgow Coma Scale at the lowest level in each subject was 14 ± 3. Among 8 subjects < ~3 months, extra-axial lesions, i.e., subdural and subarachnoid hemorrhage were predominant on MRI of 3 subjects, microhemorrhage and diffuse axonal injury (DAI) were predominant in 2, and contusion was predominant in 3. Among 17 subjects > ~3 months of injury, extra-axial predominant: 7, microhemorrhage/DAI- predominant: 5, and contusion-predominant: 5. Among 7 subjects > ~3 months with extra axial-predominant lesions, two had large hemorrhage expanding to one hemisphere, which required surgical drainage. TSPO was measured as VT using 11C-PBR28 and metabolite-corrected arterial input function. Four subjects < ~3 months of injury had PET scans at two time points; 3 subjects (2 with microhemorrhage/DAI and 1 with contusion) at ~2 weeks and ~3 months of injury and 1 subject at ~2 weeks and ~1 year.
Results PET and MRI showed markedly different findings in some but not all subjects. One of the two subjects with large extra-axial hemorrhage showed widespread ~20% increase of TSPO despite not having MRI visible lesions in brain parenchyma (Fig. 1). This subject with increased TSPO showed MRI-contrast enhancement of the meninges in the injured hemisphere, suggesting persistent extra-axial inflammation. Changes in TSPO were not detectable (within ~5% of the contralateral side) in the other subjects with extra-axial hemorrhage. TSPO around microhemorrhage/DAI showed time-related changes, which MRI did not detect. Of the two subjects who had PET scans at two time points within < ~3 months, one showed ~15% increase of TSPO only at 2 weeks but not at 3 months (Fig. 2) while the other showed increase of TSPO over time, TSPO at 3 months was 50% greater than that at 2 weeks. None with microhemorrhage/DAI who had a PET scan > ~3 months, mostly 1 - 3 years after injury, showed detectable increase in TSPO indicating that increase in TSPO in microhemorrhage/DAI is temporal. Changes in TSPO after contusion were mostly within expectations from the MRI findings. Contusion size was more predictive of positive PET findings while the timing of PET was not. Regardless of the time since injury, larger contusions tended to show greater increase in TSPO.
Conclusions The complexity of TBI is reflected in diverse findings on MRI, and some may be more relevant to secondary inflammation than others. We have found that in some patients, but not all, inflammation can be detected with TSPO in proximity to regions of focal injury. The inflammatory response also varies over time and preliminary data suggest that inflammatory changes may also occur remote to a focal lesion. Therefore, PET imaging of TSPO may identify patients in whom post-traumatic brain inflammation is a significant component of the tissue response to injury which cannot be identified by MRI alone.