CSF 5-HIAA detects secondary hypoxic insults in humans with traumatic spinal cord injuries

Abstract Project Summary and Abstract. Over 17,000 new traumatic spinal cord injuries occur in the United States each year. Following the initial traumatic insult (i.e. primary injury), blood vessel disruption leads to pervasive hypoxic and inflammatory cell damage (i.e. secondary injury). Our inability to detect ongoing cell damage impairs our capacity to develop effective strategies to limit debilitating secondary injuries. The fundamental goal of this proposal is to test the hypothesis that cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA), serotonin’s primary metabolite, is a reliable biomarker of secondary cell damage. Descending raphe projections deliver and store serotonin near spinal sensory and motor synapses. Due to the proximity of raphe projections to sensory and motor fibers, insults that damage sensory and motor tracts inadvertently injure raphe fibers resulting in a transient release of stored serotonin into the extracellular spinal tissue. 5-HIAA is a highly stable serotonin metabolite with CSF levels mirroring extracellular serotonin levels. Building from well-published animal data, and recent human studies from our group, we further hypothesize 5-HIAA to be a reliable biomarker for structural injury to spinal sensory/motor tracts, therefore 5-HIAA is an important tool to acutely prognosticating long-term outcomes in humans with spinal cord injuries. This study represents the first step in developing strategies to limit secondary injuries that exacerbate disability and undermine recovery potential in humans with acute traumatic spinal cord injuries. Within the first phase of this proposal we have 1) refined our understanding of acute management strategies to preserve motor control in patients with acute traumatic spinal cord injuries (Swaroop et al., 2024), 2) demonstrated our capacity to reliably measure CSF metabolites in humans (Anand et al., 2024), and 3) demonstrated 5-HIAA to be a stable molecule with spinal levels NOT influenced by the circadian cycle (Anand et al., 2024). Within this second phase of the project (R00) we will perform a proof-of-concept study evaluating CSF 5-HIAA’s sensitivity in detecting secondary insults in humans with spinal cord injuries. This study will set the foundation for a future PHASE III study in which we will compare the accuracy of CSF 5-HIAA vs standard physical exams, to monitor ongoing secondary injuries and prognosticate long-term clinical outcomes for spinal cord injury patients.