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Citation Information: J Clin Invest. 2025;135(5):e185463. https://doi.org/10.1172/JCI185463.
Abstract
BACKGROUND Rapid diagnosis to facilitate urgent intervention is critical for treatment of acute spinal cord injury (SCI). We hypothesized that a multi-analyte blood biomarker would support point-of-care SCI diagnosis, correlate with injury severity, and predict long-term neurologic outcomes.METHODS Droplet digital PCR (ddPCR) assays were designed to amplify differentially hypomethylated genomic loci in spinal cord tissue. An optimized ddPCR assay was applied to cell-free DNA (cfDNA) from plasma samples collected from prospectively enrolled acute SCI patients. Targeted proteomic profiling was also performed. Spinal cord–derived cfDNA and plasma proteins were tested for their association with SCI and ability to predict conversion in American Spinal Injury Association (ASIA) score at 6 months.RESULTS A bespoke ddPCR assay detected spinal cord–derived cfDNA in plasma of 50 patients with acute SCI (AUC: 0.89, 95% CI 0.83–0.95, P < 0.0001). Levels of cfDNA were highest in patients with the most severe injury, i.e., ASIA A, compared with those with ASIA B (P = 0.04), ASIA C (P = 0.009), and ASIA D injuries (P < 0.001). Dimensionality reduction identified 4 candidate proteins (FABP3, REST, IL-6, NF-H) that were integrated with spinal cord–derived cfDNA to derive the Spinal Cord Injury Index (SCII), which has high sensitivity and specificity for SCI diagnosis (AUC: 0.91, 95% CI 0.82–0.99, P < 0.0001), correlates with injury severity (P < 0.0001), and predicts 6-month neurologic improvement (AUC: 0.77, 95% CI 0.61–0.93, P = 0.006).CONCLUSION The detection of spinal cord–derived cfDNA and plasma protein alterations as part of a multi-analyte blood test can inform SCI diagnosis and prognosis.FUNDING North American Spine Society Young Investigator Award; Morton Cure Paralysis Fund.
Authors
Tej D. Azad, Kathleen R. Ran, Joshua D. Materi, Divyaansh Raj, Timour Al-Khindi, Sameer Gabbita, Marvin Li, Elizabeth T. Wang, A. Karim Ahmed, Megan Parker, Anita L. Kalluri, Daniel Lubelski, Christopher M. Jackson, Daniel M. Sciubba, Jon D. Weingart, Ali Bydon, Timothy F. Witham, David W. Nauen, Srinivasan Yegnasubramanian, Nicholas Theodore, Chetan Bettegowda
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