Good afternoon, and thank you very much for inviting me to present my research. Today I'll be talking about Serum Tau and P-Tau as diagnostic and prognostic tools for pediatric traumatic brain injury. I have no disclosures. First, I would like to start by acknowledging that despite multiple studies over the past decade and the discovery of numerous biomarkers, there still remains a need for a novel biomarker that can assist in outcome prediction after pediatric traumatic brain injury. A PTBI biomarker could be further developed to assist clinicians in determining injury severity, acute assessment of mortality risk, and potentially could be used as a prognosticator for long-term rehabilitation needs. The microtubule binding protein Tau functions to regulate and stabilize axonal microtubule assembly and disassembly. When Tau undergoes post-translational modifications and hyperphosphorylation, it yields P-Tau, an abnormal, insoluble Tau protein. Gradually, P-Tau forms aggregates, which progress into neurofibrillary tangles, a classical histological hallmark of the development of Tauopathies. While P-Tau is a marker for neurodegenerative disorders such as dementia, it can also be a potential biomarker for individuals with traumatic brain injury. Tau and P-Tau have been investigated in neurodegenerative diseases and adult traumatic brain injury. But there remains little research on the role in pediatric traumatic brain injury. Adult studies have shown elevations in T-Tau one hour after traumatic brain injury, with a persistence of elevated levels up to six days after injury, and normalization within eight to 12 weeks without further neurological injury. Tau has been shown to predict clinical outcomes following traumatic brain injury in adults. Initial CSF cleaved Tau protein C-Tau in patients with severe traumatic brain injury had a sensitivity of 92% and a specificity of 94% at predicting outcomes in an adult study. There was another study in concussed professional ice hockey players in which plasma T-Tau concentrations were increased one hour after injury compared with pre-season concentrations and predicted return to play with high accuracy. Initial serum Tau concentrations in children are negatively correlated with GCS scores as compared to the control group. Tau could potentially be used as a biomarker for mild traumatic brain injury and has the potential to differentiate between the various degrees of mild, GCS 13, 14 versus GCS 15. This was originally published by Stukas and Lancet. Now based on the background presented before, our group aimed to assess the utilization of Tau and P-Tau, neuronal blood-based biomarkers, as a diagnostic and prognostic tool in the setting of mild and moderate pediatric traumatic brain injury, according to the Glasgow Common Scale and the Glasgow Outcome Scale Extended Pediatrics. We have three specific aims. The first one was to determine the levels of Tau and P-Tau in the serum of pediatric traumatic brain injury patients. The second one was to determine the biomarker potential of Tau and P-Tau 181 as a diagnostic fluid biomarker of pediatric traumatic brain injury. And the third one was to identify the biomarker potential of Tau and P-Tau as a prognostic fluid biomarker of PTBI. This was a prospective observational study. We included 29 patients aged 0 to 18 years who sustained a mild or moderate pediatric traumatic brain injury, GCS 9 to 15, and 19 healthy controls. We obtained serum samples of Tau and P-Tau, and these samples were analyzed at the time of enrollment, which we call zero hours. Then, subsequently, we collected blood samples at 24 and 48 hours post-injury. Receiver operating characteristics and statistical comparisons were performed to analyze plasma biomarker concentrations and GCS severity, as well as binary GOSEP outcomes. 5 to 8 was unfavorable, 1 to 4 was favorable, which was evaluated at 2 to 6 weeks, 6 to 9 months, and 12 months post-injury. The data was analyzed using PRISM. Now, let's talk a little bit about the results, which is the exciting part. Now, let's look at the Tau profile in pediatric traumatic brain injury patients with different severities categorized by initial GCS. In the first graph, we have the concentration on the y-axis in picograms per ml, and in the x-axis, we have the different severities at 0, 24, and 48 hours. We can see their statistical significance when we compare mild traumatic brain injury at zero hours versus healthy controls, as well as the combination of mild and moderate Tau at zero hours versus healthy controls, and lastly, mild and moderate combined at 24 hours versus healthy controls. Then we have respective ROCs for Tau at zero hours for mild GCS with an area under the curve of 0.8, followed by Tau at zero and 24 for mild and moderate combined, in which we have Tau at zero hours with an AUC of 0.84 and Tau at 24 hours with an AUC of 0.82. Then we're going to look at the P-Tau 181 profile in pediatric traumatic brain injury patients with, same, different severities categorized by initial GCS. Here we have statistical significance in mild at zero hours versus healthy control, mild and moderate at zero hours, as well as mild at 48 hours and mild and moderate together at 48 hours. Again, we have the respective ROCs with an AUC of 0.86 for P-Tau 181 at zero hours in the mild-only cohort and 0.98 for P-Tau at 48 hours in the mild-only cohort. When we combine mild and moderate together, we have an AUC of 0.88 for P-Tau at zero hours and then an AUC of 0.93 for P-Tau at 48 hours. Now let's look at the initial serum levels of P-Tau 181 as predictor functional outcome when we average follow-ups at two to six weeks based on the GOS-E pediatrics. Again, in the y-axis, we have the concentration in picograms per mL, and then we look at favorable versus unfavorable outcome. We see that there is statistical significance for P-Tau when measured at zero hours, and then in the ROC, we have an area under the curve of 0.9. When we look at P-Tau again at zero hours, but looking at the follow-ups at six to nine months, we also have statistical significance and an area under the curve of 0.8. Now let's look at P-Tau at zero hours when the follow-ups were done at 12 months. We have a statistical significance as well. Then our ROC shows an area under the curve of 0.95. Now let's look at Tau. When we analyzed Tau, we didn't have statistical significance at two to six weeks or six to nine months. However, we did find a statistical significance when measured at zero hours and compared with the 12-month outcomes. In here, we can see an ROC that demonstrates an AUC of one. Now what can we conclude from this research? Well, first, that serum Tau and P-Tau levels were elevated in mild and combined mild and moderate pediatric traumatic brain injury subjects at zero hours post-injury compared to healthy controls. Then measuring Tau and P-Tau at the time of initial injury may be able to assist with mild pediatric traumatic brain injury diagnosis. And lastly, examining the relationship between elevations of these proteins following pediatric traumatic brain injury with the Glasgow Outcomes Scale Pediatrics at two to six weeks, six to nine months, and 12 months post-injury could potentially predict neurological outcomes. I would like to thank all my collaborators and mentors. It takes a village and the right tool to get the job done, and I am very fortunate to have an amazing team helping with this project. Thank you very much to the University of Florida, the University of Miami, the Miami Project of Cure Paralysis, the CTSI, Hull Children's Hospital, the Melman Center, and of course, the Society of Critical Care Medicine for this invitation. Thank you so much.

serum Tau

P-Tau

biomarkers

pediatric traumatic brain injury

outcome prediction