Axonal degeneration is a critical, early event in many acute and chronic neurological disorders. It has been consistently observed after traumatic brain injury, but whether axon degeneration is a driver of traumatic brain injury remains unclear. Molecular pathways underlying the pathology of traumatic brain injury have not been defined, and there is no efficacious treatment for traumatic brain injury. Here we show that mice lacking the mouse Toll receptor adaptorSarm1(sterile alpha/Armadillo/Toll-Interleukin receptor homology domain protein) gene, a key mediator of Wallerian degeneration, demonstrate multiple improved traumatic brain injury-associated phenotypes after injury in a closed-head mild traumatic brain injury model.Sarm1(-/-)mice developed fewer beta-amyloid precursor protein aggregates in axons of the corpus callosum after traumatic brain injury as compared toSarm1(+/+)mice. Furthermore, mice lackingSarm1had reduced plasma concentrations of the phophorylated axonal neurofilament subunit H, indicating that axonal integrity is maintained after traumatic brain injury. Strikingly, whereas wild-type mice exibited a number of behavioural deficits after traumatic brain injury, we observed a strong, early preservation of neurological function inSarm1(-/-)animals. Finally, usingin vivoproton magnetic resonance spectroscopy we found tissue signatures consistent with substantially preserved neuronal energy metabolism inSarm1(-/-)mice compared to controls immediately following traumatic brain injury. Our results indicate that the SARM1-mediated prodegenerative pathway promotes pathogenesis in traumatic brain injury and suggest that anti-SARM1 therapeutics are a viable approach for preserving neurological function after traumatic brain injury.

Objective: Surrogate decision-makers (“surrogates”) and physicians of incapacitated patients have different views of prognosis and how it should be communicated, but this has not been investigated in neurocritically-ill patients. We examined communication preferences in surrogates and physician practices during the outcome prognostication for critically-ill traumatic brain injury (ciTBI) patients in neuroICUs. Design: Qualitative study using in-person semi-structured interviews with surrogates of ciTBI patients and physicians with expertise in TBI. Setting: Two neuroICUs at two level-1 trauma centers (surrogates); seven academic U.S. medical centers (physicians). Subjects: Sixteen surrogates for 15 ciTBI patients and 20 attending physicians from neurocritical care, neurosurgery, trauma and palliative care. Interventions: Not applicable. Measurements and Main Results: We used qualitative content analysis and descriptive statistics of transcribed interviews to identify themes in surrogates and physicians. The majority of surrogates (82%) preferred numeric estimates describing the patient’s prognosis, as they felt it would limit prognostic uncertainty, which, in turn, surrogates perceived as frustrating. On the other hand, 75% of the physicians reported intentionally omitting numeric estimates during prognostication meetings due to low confidence in family members’ abilities to appropriately interpret probabilities, worry about creating false hope, and distrust in the accuracy and data quality of existing TBI outcome models. Physicians felt that TBI outcome models are for research only and should not be applied to individual patients. Surrogates valued compassion during prognostication discussions, and acceptance of their goals-of-care decision by clinicians. Physicians and surrogates agreed on avoiding false hope. Conclusions: We identified fundamental differences in preferences for the communication of prognostic information between surrogates of ciTBI patients and physicians during goals-of-care discussions. A decision aid could potentially bridge this chasm by providing surrogates consistent and patient-centered information, however, with qualitative rather than quantitative estimates of ciTBI prognosis and an open disclosure of uncertainty.

Traumatic brain injury (TBI) is a leading cause of disability worldwide. Annually, 150 to 200/1,000,000 people become disabled as a result of brain trauma. Axonal degeneration is a critical, early event following TBI of all severities but whether axon degeneration is a driver of TBI remains unclear. Molecular pathways underlying the pathology of TBI have not been defined and there is no efficacious treatment for TBI. Despite this significant societal impact, surprisingly little is known about the molecular mechanisms that actively drive axon degeneration in any context and particularly following TBI. Although severe brain injury may cause immediate disruption of axons (primary axotomy), it is now recognized that the most frequent form of traumatic axonal injury (TAI) is mediated by a cascade of events that ultimately result in secondary axonal disconnection (secondary axotomy) within hours to days. Proposed mechanisms include immediate post-traumatic cytoskeletal destabilization as a direct result of mechanical breakage of microtubules, as well as catastrophic local calcium dysregulation resulting in microtubule depolymerization, impaired axonal transport, unmitigated accumulation of cargoes, local axonal swelling, and finally disconnection. The portion of the axon that is distal to the axotomy site remains initially morphologically intact. However, it undergoes sudden rapid fragmentation along its full distal length ~72 h after the original axotomy, a process termed Wallerian degeneration. Remarkably, mice mutant for the Wallerian degeneration slow (Wlds) protein exhibit ~tenfold (for 2–3 weeks) suppressed Wallerian degeneration. Yet, pharmacological replication of the Wlds mechanism has proven difficult. Further, no one has studied whether Wlds protects from TAI. Lastly, owing to Wlds presumed gain-of-function and its absence in wild-type animals, direct evidence in support of a putative endogenous axon death signaling pathway is lacking, which is critical to identify original treatment targets and the development of viable therapeutic approaches. Novel insight into the pathophysiology of Wallerian degeneration was gained by the discovery that mutant Drosophila flies lacking dSarm (sterile a/Armadillo/Toll-Interleukin receptor homology domain protein) cell-autonomously recapitulated the Wlds phenotype. The pro-degenerative function of the dSarm gene (and its mouse homolog Sarm1) is widespread in mammals as shown by in vitro protection of superior cervical ganglion, dorsal root ganglion, and cortical neuron axons, as well as remarkable in-vivo long-term survival (>2 weeks) of transected sciatic mouse Sarm1 null axons. Although the molecular mechanism of function remains to be clarified, its discovery provides direct evidence that Sarm1 is the first endogenous gene required for Wallerian degeneration, driving a highly conserved genetic axon death program. The central goals of this thesis were to determine (1) whether post-traumatic axonal integrity is preserved in mice lacking Sarm1, and (2) whether loss of Sarm1 is associated with improved functional outcome after TBI. I show that mice lacking the mouse Toll receptor adaptor Sarm1 gene demonstrate multiple improved TBI-associated phenotypes after injury in a closed-head mild TBI model. Sarm1-/- mice developed fewer beta amyloid precursor protein (βAPP) aggregates in axons of the corpus callosum after TBI as compared to Sarm1+/+ mice. Furthermore, mice lacking Sarm1 had reduced plasma concentrations of the phosphorylated axonal neurofilament subunit H, indicating that axonal integrity is maintained after TBI. Strikingly, whereas wild type mice exhibited a number of behavioral deficits after TBI, I observed a strong, early preservation of neurological function in Sarm1-/- animals. Finally, using in vivo proton magnetic resonance spectroscopy, I found tissue signatures consistent with substantially preserved neuronal energy metabolism in Sarm1-/- mice compared to controls immediately following TBI. My results indicate that the Sarm1-mediated prodegenerative pathway promotes pathogenesis in TBI and suggest that anti-Sarm1 therapeutics are a viable approach for preserving neurological function after TBI.

The Glasgow Coma Scale (GCS) has limited utility in intubated patients due to the inability to assign verbal subscores. The verbal subscore can be derived from the eye and motor subscores using a mathematical model, but the advantage of this method and its use in outcome prognostication in traumatic brain injury (TBI) patients remains unknown. We compared the validated "Core+CT"-IMPACT-model performance in 251 intubated TBI patients prospectively enrolled in the longitudinal OPTIMISM study between November 2009 and May 2015 when substituting the original motor GCS (mGCS) with the total estimated GCS (teGCS; with estimated verbal subscore). We hypothesized that model performance would improve with teGCS. Glasgow Outcome Scale (GOS) scores were assessed at 3 and 12 months by trained interviewers. In the complete case analysis, there was no statistically or clinically significant difference in the discrimination (C-statistic) at either time-point using the mGCS versus the teGCS (3 months: 0.893 vs. 0.871;12 months: 0.926 vs. 0.92). At 3 months, IMPACT-model calibration was excellent with mGCS and teGCS (Hosmer-Lemeshow "goodness-of-fit" chi square p value 0.9293 and 0.9934, respectively); it was adequate at 12 months with teGCS (0.5893) but low with mGCS (0.0158), possibly related to diminished power at 12 months. At both time-points, motor GCS contributed more to the variability of outcome (Nagelkerke DeltaR(2)) than teGCS (3 months: 5.8% vs. 0.4%; 12 months: 5% vs. 2.6%). The sensitivity analysis with imputed missing outcomes yielded similar results, with improved calibration for both GCS variants. In our cohort of intubated TBI patients, there was no statistically or clinically meaningful improvement in the IMPACT-model performance by substituting the original mGCS with teGCS.