Evidence of Chronic Complement Activation in Asymptomatic Pediatric Brain Injury Patients: A Pilot Study

Abstract

Physical insult from a mild Traumatic Brain Injury (mTBI) leads to changes in blood flow in the brain and measurable changes in white matter, suggesting a physiological basis for chronic symptom presentation. Post-traumatic headache (PTH) is frequently reported by persons after an mTBI that may persist beyond the acute period (>3 months). It remains unclear whether ongoing inflammation may contribute to the clinical trajectory of PTH. We recruited a cohort of pediatric subjects with PTH who had an acute or a persistent clinical trajectory, each around the 3-month post-injury time point, as well as a group of age and sex-matched healthy controls. We collected salivary markers of mRNA expression as well as brain imaging and psychological testing. The persistent PTH group showed the highest levels of psychological burden and pain symptom reporting. Our data suggest that the acute and persistent PTH cohort had elevated levels of complement factors relative to healthy controls. The greatest change in mRNA expression was found in the acute-PTH cohort wherein the complement cascade and markers of vascular health showed a prominent role for C1Q in PTH pathophysiology. These findings (1) underscore a prolonged engagement of what is normally a healthy response and (2) show that a persistent PTH symptom trajectory may parallel a poorly regulated inflammatory response.

Keywords: brain injury; inflammation; pediatrics.

Figure 1

Self-reported symptoms. Findings are outlined for the three cohorts using mean and standard deviations for the main mTBI and pain questionnaires. mTBI symptom reporting is provided for the Impact and Rivermead mTBI surveys. * indicates a p-value less than 0.05.

Figure 2

Initiation and Regulation of the complement cascade. Markers are presented for factors that were found for at least one cohort to be above detectable limits. Samples were found to be statistically significant (filled boxes or circles) if they had p-values < 0.05. Error bars represent one standard deviation.

Figure 3

Summary of findings from the Principal Component Analysis. The screeplot (left panel), cumulative variance plot (middle panel), and the variance from the first two dimensions (right panel) with ellipses to identify the respective study cohorts are shown.

Figure 4

Five highest contributions to the first component from the PCA analysis of the complement cascade. The log expression values were evaluated in each cohort relative to healthy control data, with * indicating a p-value less than 0.05.

Figure 5

Regional cross-modal analysis for the bilateral thalamus. Data is presented for cerebral blood flow (left), the correlation between cerebral blood flow and self-reported headache symptoms (middle), and the correlation between CBF and inflammatory markers (right).