Traumatic axonal injury (TAI) following traumatic brain injury (TBI) contributes to morbidity and mortality. TAI involves intra-axonal changes assumed to progress to impaired axonal transport (IAT), disconnection, and axonal bulb formation. Immunocytochemical studies employing antibodies to amyloid precursor protein (APP), a marker of IAT and RMO14, a marker of neurofilament compaction (NFC), have shown that TAI involves both NFC and IAT, with the suggestion that NFC leads to IAT. Recently, new data has suggested that NFC may occur independently of IAT. The objective of this study was to determine quantitatively the precise relationship between NFC and IAT. Following TBI, rats were studied at 30 min, 3 h, and 24 h. Using single-label immunocytochemistry employing the antibodies RM014, APP, or a combined labeling strategy targeting APP/RMO14 in aggregate, the immunoreactive (IR) profiles were counted in the corticospinal tract (CSpT) and medial lemniscus (ML). In the CSpT, the number of axons demonstrating RMO14-IR approximated the number of axons showing APP-IR, with the APP-IR population showing a significant increase over 24 h (p < 0.05). The sum of both single-label counts equaled the aggregate APP/RMO14 numbers, demonstrating little relationship between NFC and IAT. In the ML, 75% of fibers demonstrated a separation of APP-IR and NFC-IR; however, 25% of the ML fibers showed co-localization of APP-IR and RMO14. The results of these studies indicate that, in the majority of damaged axons, NFC is not associated with IAT. Our findings argue for the use of multiple markers when evaluating the extent of TAI or the efficacy of therapies targeting the treatment of TAI.

Traumatic brain injury (TBI) is one of the leading causes of death and disability around the world. The lack of validated biomarkers for TBI is a major impediment to developing effective therapies and improving clinical practice, as well as stimulating much work in this area. In this review, we focus on different settings of TBI management where blood or cerebrospinal fluid (CSF) biomarkers could be utilized for predicting clinically-relevant consequences and guiding management decisions. Requirements that the biomarker must fulfill differ based on the intended context of use (CoU). Specifically, we focus on fluid biomarkers in order to: (1) identify patients who may require acute neuroimaging (cranial computerized tomography (CT) or magnetic resonance imaging (MRI); (2) select patients at risk for secondary brain injury processes; (3) aid in counseling patients about their symptoms at discharge; (4) identify patients at risk for developing postconcussive syndrome (PCS), posttraumatic epilepsy (PTE) or chronic traumatic encephalopathy (CTE); (5) predict outcomes with respect to poor or good recovery; (6) inform counseling as to return to work (RTW) or to play. Despite significant advances already made from biomarker-based studies of TBI, there is an immediate need for further large-scale studies focused on identifying and innovating sensitive and reliable TBI biomarkers. These studies should be designed with the intended CoU in mind.

The neuropathology of traumatic brain injury (TB) is diverse, including primary injury to neurons, axons, glial cells, vascular structures, and secondary processes, such as edema and inflammation that vary between individual patients. Traumatic microvascular injury is an important endophenotype of TBI-related injury. We studied patients who sustained a TBI requiring ER evaluation and had an MRI performed within 48 h of injury. We classified patients into 3 groups based on their MRI findings: (1) those that had evidence of traumatic microvascular injury on susceptibility or diffusion weighted MRI sequences without frank hemorrhage [Traumatic Vascular Injury (TVI) group; 20 subjects]. (2) those who had evidence of intraparenchymal, subdural, epidural, or subarachnoid hemorrhage [Traumatic Hemorrhage (TH) group; 26 subjects], and (3) those who had no traumatic injuries detected by MRI [MRI-negative group; 30 subjects]. We then measured plasma protein biomarkers of vascular injury [von Willebrand Factor (vWF) or cellular fibronectin (cFn)] and axonal injury (phosphorylated neurofilament heavy chain; pNF-H). We found that the TVI group was characterized by decreased expression of plasma vWF ( p < 0.05 compared to MRI-negative group; p < 0.00001 compared to TH group) ≤48 h after injury. cFN was no different between groups ≤48 h after injury, but was increased in the TVI group compared to the MRI-negative ( p < 0.00001) and TH ( p < 0.00001) groups when measured >48 h from injury. pNF-H was increased in both the TH and TVI groups compared to the MRI-negative group ≤48 h from injury. When we used the MRI grouping and molecular biomarkers in a model to predict Glasgow Outcome Scale-Extended (GOS-E) score at 30–90 days, we found that inclusion of the imaging data and biomarkers substantially improved the ability to predict a good outcome over clinical information alone. These data indicate that there is a distinct, vascular-predominant endophenotype in a subset of patients who sustain a TBI and that these injuries are characterized by a specific biomarker profile. Further work to will be needed to determine whether these biomarkers can be useful as predictive and pharmacodynamic biomarkers for vascular-directed therapies after TBI.

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