Acute spinal cord injury (SCI) is difficult to diagnose, and treatment options depend upon accurate information on the severity and level of injury, as well as on the presence of co-morbidities and polytrauma. Acute treatment of SCI is hampered by the lack of evidence-based treatment options and by the difficulty of categorizing acute patients who may be unconscious or unable to provide a reliable early neurological exam. We are in the midst of a Congressionally Directed Medical Research Programs (CDMRP) Spinal Cord Injury Research Program (SCRIRP)-supported prospective observational study of acute SCI at the Zuckerberg San Francisco General Hospital (ZSFG) called “Transforming Research and Clinical Knowledge in SCI” (TRACK-SCI). Mean time from Emergency Medical Technician (EMT) contact to admission is less than 20 minutes, providing an opportunity to obtain hyper-acute data and test for the earliest predictors of outcome. The goal of this proposal is to leverage our developed infrastructure to focus on early high-quality magnetic resonance imaging (MRI) and physiological data from both the operating room (OR) and intensive care unit (ICU), with good outcome data 6 and 12 months after SCI as well as a search for diagnostic and prognostic predictors related to early tissue damage and protection. Data from our current study show the feasibility of obtaining high quality RNA and RNA sequencing reads from early and sequential blood draws. This proposal is based on strong preliminary data gathered during the first 3 years of SC150198 and represents an extension to continue to collect data, given the promise from those data that early critical care variables and longitudinal RNAseq gene expression in peripheral blood cells after SCI will yield useful predictors of severity and long-term outcome.

Our overarching hypothesis is based on the premise that the spinal cord is especially vulnerable to secondary injury in the first hours and days following injury, and that secondary injury can be minimized by identifying and optimizing the early critical care variables that are most important in determining recovery. Our current study has taken a broad approach to identifying (1) sources of potential secondary injury (e.g., hypo- or hypertension, length of time of cord compression, (2) early clinical measures that may be prognostic (e.g., MRI), and (3) how these relate to outcomes, defined as Asia Impairment Scale (AIS) scores early on (e.g., at discharge) and late after injury (e.g., Neuro Quality of Life, Spinal Cord Independence Measure, late ISNCSCI exams, bladder/bowel function, etc.).

Our secondary hypothesis is that white blood cells (WBCs) act as “sentinels,” encoding critical biological information related to injury severity, repair, and long-term recovery after SCI, and that we can query this information using RNA sequencing to provide SCI-induced gene expression patterns that can serve as biological indicators of injury severity and prognosis, and that could be validated to provide useful biomarkers for diagnosis, prognosis, and treatment.

We expect that we will continue to identify early critical care variables and RNA readouts that can be translated into usable convenient testing platforms using microfluidics or other approaches and that will yield new insights into SCI pathophysiology, and that can be back-translated into preclinical studies of mechanism as well as be used as surrogate markers of therapeutic interventions. We have made significant progress toward the goals of SC150198, which are described in detail in the proposal. While we are still enrolling subjects and curating the prospective data set, we have some preliminary findings that, if confirmed and validated in our expansion of TRACK-SCI, may have great importance for providing new evidence-based practice guidelines as well as new insights into the pathophysiology of secondary injury that may lead to new treatment strategies.