By analyzing DNA and proteins in the blood of people with and without acute spinal cord injuries (SCIs), researchers at the Johns Hopkins University School of Medicine have developed a novel blood test that has the potential to rapidly predict severity and likelihood of sensory and motor recovery within six months in a cost-effective manner.
The National Institutes of Health estimates 18,000 people experience SCIs each year in the United States, costing Americans over $9.7 billion annually, as SCI causes immense emotional and financial strain for patients and caregivers. SCI diagnosis and potential recovery rely on extensive clinical examinations and advanced imaging, a time-consuming, costly process that is especially challenging for patients with SCI-related complications. By analyzing DNA and proteins in the blood of people with and without acute spinal cord injuries (SCIs), researchers at the Johns Hopkins University School of Medicine have developed a novel blood test that has the potential to rapidly predict severity and likelihood of sensory and motor recovery within six months in a cost-effective manner.
Clinicians have long sought a rapid, minimally invasive diagnostic method that confirms injury, severity and recovery potential. The novel blood test described in a report published in the March issue of The Journal of Clinical Investigation may fill this critical gap in care.
"If you have a spinal cord injury, your main question is simple: Am I going to walk again?" says lead study author and neurosurgery chief resident Tej D. Azad, M.D., M.S. "With the new blood test, we are trying to bring a precision medicine framework to spinal cord injury with something that tells you about injury severity and can hopefully predict neurological recovery."
Classically, blood tests have not been considered to offer insights into the spine due to the blood-brain barrier - a protective layer of cells that that blocks most viruses, bacteria and other harmful substances from reaching the brain through the blood. However, researchers hypothesized that SCI causes measurable disruptions in the blood-brain barrier that are potentially detectable in a blood test.
To detect such biomarkers of SCI, the researchers built on recent advances in cancer biomarker development, where liquid biopsies of blood detect cell-free DNA (cfDNA) and certain protein levels guide targeted treatments for individual patients while also offering ways to monitor treatment response and disease progression.
"Using blood-based biomarkers for cancer diagnosis and progression has changed the practice of oncology," says co-senior study author Nicholas Theodore, M.D., director of the Johns Hopkins Neurosurgical Spine Center. "Utilizing similar technology, this test is truly an example of personalized medicine in traumatic injury."
Researchers defined the fingerprint of spinal cord DNA using blood samples from 50 patients with acute SCI and 25 patients without injury, of which 68% (51 patients) were male and 32% (24 patients) were female. Researchers also observed that cfDNA levels in blood samples correlated with the standard American Spinal Injury Association (ASIA) scale used to assess SCI severity based on motor and sensory function. Higher cfDNA concentrations were found in the ASIA A group - representing no sensation or function of motor skills - compared to less severe injuries with groups B (P = 0.04), C (P = 0.009), and D (P < 0.001), suggesting that greater spinal cord damage releases more cfDNA into the bloodstream. To further refine the blood test's accuracy, researchers identified four key blood plasma proteins - FABP3, REST, IL-6 and NF-H - that were elevated in patients with SCI.
The investigators call the resulting combination blood test the Spinal Cord Injury Index (SCII). When compared to ASIA groups, the results of SCII aligned completely with severity of injury and what would be seen on MRI scans and physical evaluations.
"These findings highlight the importance of a multi-analyte approach," says senior study author and the Jennison and Novak Families Professor of Neurosurgery, Chetan Bettegowda, M.D., Ph.D. "Combining both DNA and protein-based biomarkers improves the test performance and biological relevance."
Patients whose blood was used in the study were followed for six months to see if their ASIA grade improved. The SCII effectively predicted with 77% accuracy which patients would show neurologic improvement. This suggests that the new blood test may accurately forecast long-term recovery for most patients, a central focus and concern for patients with SCI and their caregivers.
Researchers say using the SCII to monitor these biomarkers over time could further assist in measuring the effectiveness of treatment options and inform personalized care, as liquid biopsies inform care for cancer patients.
"We are interested in bringing a precision medicine framework to spinal cord injury," says Azad. "By building this type of blood test, we can begin to sub-stratify these traditional groups, use therapies that may be more beneficial, and for patients who have most severe injury, we can expedite getting them into clinical trials," says Azad.
This multi-analyte blood test is a promising step toward next generation diagnostics for SCI and personalized medicine in traumatic injury. Bettegowda says further studies are required, as the team is now hoping to test the blood markers in multi-center clinical trials and study ways to improve its performance.
Other scientists who contributed to this research are Kathleen Ran, Joshua Materi, Divyaansh Raj, Timour Al-Khindi, Sameer Gabbita, Marvin Li, Elizabeth Wang, A. Karim Ahmed, Megan Parker, Anita Kalluri, Daniel Lubelski, Christopher Jackson, Daniel Sciubba, Jon Weingart, Ali Bydon, Timothy Witham, David Nauen and Srinivasan Yegnasubramanian.
Daniel Lubelski reported personal fees from Carbofix, Icotec, and Mindset Medical; and grants from Dilon Technologies outside the submitted work. Christopher Jackson is a consultant for Egret Therapeutics with equity interests in the company. He is an inventor on a patent filed by The Johns Hopkins University for using immune checkpoint agonists to treat cerebrovascular disorders. He receives research support from Biohaven, InCephalo, and Grifols. Daniel Sciubba reported personal fees from DePuy, Medtronic, Stryker, NuVasive and Baxter outside the submitted work. Nicholas Theodore receives royalties from and owns stock in Globus Medical, is a consultant for Globus Medical and has served on the scientific advisory board for Globus Medical. Chetan Bettegowda is a consultant for Depuy-Synthes, Bionaut Labs, Haystack Oncology and Privo Technologies. Chetan Bettegowda is a co-founder of OrisDx and Belay Diagnostics.
All other authors declare that they have no potential conflicts of interest.
Funding for this research was provided by the North American Spine Society Young Investigator Award (Tej Azad, Nicholas Theodore) and the Morton Cure Paralysis Fund (Chetan Bettegowda, Tej Azad, Nicholas Theodore).
