Three Months Follow-Up of Mild Traumatic Brain Injury in Rats: A Combined [¹⁸F]FDG and [¹¹C]PK11195 PET Study

Aim: Mild traumatic brain injury (mTBI) is the most common cause of head trauma and it is especially relevant in adolescents and sport activities. However, the time course of its functional pathology is not well defined. In this study the consequences of mTBI were evaluated in a rat model over a period of 3 months. The presence of neuroinflammation ([¹¹C]PK11195) and changes in brain metabolism ([¹⁸F]FDG) were determined using small animal PET imaging.
Material and Methods: A weight-drop mTBI model was used to replicate the pathological features seen in humans. Male Sprague-Dawley rats were divided into sham (n=8) and trauma (n=8) groups. PET imaging and behavioral tests (i.e. open field, object recognition and Y-maze) were performed at different time points after induction of the trauma: acute stage (9-12 days), 1 and 3 months. Differences between groups in the bodyweight and behavioral scores were analyzed using the Generalized Estimating Equations model and p<0.05 were considered significant. Differences in tracer uptake were analyzed with a voxel-based analysis. T-maps were interrogated with uncorrected p<0.005 and 200 threshold voxels; only clusters with FDR-corrected p<0.05 were considered significant.
Results: Trauma induction did not result in death, skull fracture or neurological suppression of reflexes. A statistically significant decrease in gained body weight was observed in mTBI group (p=0.003). No statistical differences were found between groups in any of the behavioral tests. In the voxel-based analysis, a comparison between mTBI and sham groups was performed at each time point. A neuroinflammatory process was detected only in the acute phase, with significantly
higher [¹¹C]PK11195 uptake located bilaterally in the pons, medulla, cerebellum, hypothalamus, caudate, putamen, and the right amygdala. Increased regional [¹⁸F]FDG uptake in mTBI rats was detected in all time points bilaterally in the medulla, in addition to an increased uptake at 3 months in the left motor, somatosensory, visual and parietal cortices. Moreover, decreased uptake was detected during the follow-up period in the thalamus, internal capsule, amygdala, caudate, putamen, globus pallidus, hippocampus, and somatosensory cortex.
Conclusion: Alterations in the regional glucose metabolism of the brain extend for a period of at least 3 months in regions that seem to present an acute  neuroinflammatory response to the trauma. The presence of these long-lasting functional alterations must be considered carefully in the context of mTBI, especially in sports and recreational activities where patients may be exposed to a repeated head trauma.