Validation of Structural, Molecular, and Functional Imaging Biomarkers in Spinal Cord Injury in Nonhuman Primates

Principal Investigator: GORE, JOHN C
Program: SCIRP
Proposal Number: SC160154
Award Number: W81XWH-17-1-0304
Funding Mechanism: Investigator-Initiated Research Award
Partnering Awards:
Award Amount: $782,283.61


Spinal cord injuries (SCIs) are one of the most prevalent causes for permanent disability of military personnel (and their families) in the United States, and are often the result of a sudden, traumatic, and life-changing event. Traumatic SCI can lead to diverse and widespread nerve damage that affects multiple functions -- the ability to sense touch or heat, the ability to control motor movements (often corresponding to paralysis), and the loss of control of essential bodily functions such as bowel and urinary functions. SCI often leads to long-term disability and has devastating consequences for patients due to severe impairments of normal functions, and thus a significant impact on quality of life, life expectancy, and economic burden. There is therefore a compelling need for more research into how to treat SCI effectively and for methods that can be used to evaluate whether treatments are working. However, some patients show spontaneous recovery of some functions in the period after their injuries, demonstrating an ability of the body to heal itself to some degree. This process of spontaneous repair of damaged SC is poorly understood, yet could form the basis for new insights into how to improve the treatment of injured spines. A primary obstacle to understanding the process is a lack of appropriate methods for tracking changes in spinal cords over time. Such information is critical for a basic understanding of recovery processes and for determining the optimal time window, targets, and effectiveness of therapeutic interventions. The ultimate applicability of the research proposed is that it will establish and validate the role of novel, non-invasive magnetic resonance imaging (MRI) methods as biomarkers of the structural and functional integrity of the spinal cord, to be used as a tool to guide the development and application of treatments, and to increase our understanding of spontaneous repair mechanisms.

MRI is firmly established as the single most useful imaging technique available for evaluating soft tissue injuries and is in widespread use for assessing spinal cord injuries. However, conventional MRI provides no insight into the functional integrity of the cord, and documented changes in conventional MRI features show little correlation with the severity of injury or the processes that arise during recovery. However, recent developments in MRI acquisition methods have led to the potential for measuring functional and structural changes in the cord not previously available. We believe that combinations of novel, advanced MRI methods can provide unique insights into SCI progression, especially into the functional integrity of grey matter and microstructural and biochemical changes in white matter. We propose to implement non-invasive multiparametric MRI at high field to assess changes in structural, functional, and cellular/molecular properties of SCI over time in a controlled monkey model of injury that is directly relevant to humans, and to verify how these changes predict and correlate with behavioral recovery. The result will be the development and validation of a set of MR methods that can be employed anywhere and that will provide unique and unprecedented information on the evolution of repair processes in the spinal cord post-injury.

There will be direct clinical benefits of having a method to track changes in recovering cords and to provide new information on cord function and structure. Such information is critical for evaluating the efficacy of individual treatment programs, and for determining the optimal time window, targets, and effectiveness of therapeutic interventions. All patients with traumatic SCI are likely to benefit from the understanding obtained of the nature of spontaneous repair, and individual patients will benefit by using MRI during the course of their treatment.

These studies are directly translatable to human patients. If the monkey data confirm the interpretation of MRI as direct indicators of functionally and structurally relevant changes within the cord, the methods developed can be implemented on clinical 3T MRI scanners within a short period (~1 year) and a clinical trial to validate the conclusions from non-human primates could be started.