Monitoring Early Acute Therapeutic Responses with MRI in Preclinical Spinal Cord Injury
Abstract
The overall objective of these proposed studies using an animal model is to promote improved medical care of spinal cord injury (SCI) in the early acute setting after injury. Medical care in the acute setting is believed to be the most critical period to promote better long-term outcomes, since the initial injury leads to a vicious cycle of swelling that exacerbates the injury and damage to the cord. Unfortunately, none of the therapies developed in animal models have led to success in clinical trials for SCI. This failure of translation can be at least partially attributed to the heterogeneity of human SCI along with the lack of tools to predict whether a given patient will benefit from an intervention to regain neurological function. The motivation of the studies in this proposal is driven comparisons to another acute neurological event—stroke—in which imaging has become an essential medical tool to guide appropriate treatment as early as possible to each patient through an established “algorithm-of-care”. By incorporating imaging biomarkers to identify patients most likely to benefit from an intervention, clinical trials in stroke have seen tremendous success in recent years. On the other hand, imaging has not been adequately adopted to clinical trials for SCI to monitor treatment effects or identify patients in which therapies may be useful. The proposed studies will employ an animal model of SCI within the framework of a preclinical trial using imaging biomarkers in combination with therapies with established success in animal models. The first primary outcome is to identify the signature imaging features of SCI that predict the likelihood for recovery of function. The second outcome is to establish the imaging biomarkers, using magnetic resonance imaging (MRI) in particular, that determine whether a subject is likely to benefit from a given treatment. The third outcome is to demonstrate whether MRI can detect a short-term treatment effect that predicts its long-term success on neurological function. Pre-treatment MRI will be performed acutely at 6 hours after the injury, followed by initiation of a pharmacological or surgical treatment and follow-up MRI again at 48 hours and 90 days post-injury. Behavioral neurological outcomes measured throughout the recovery period. Critically, all studies will be randomized and fully blinded to injury severity and treatment group to mimic the blinding inherent in well designed clinical trials. Furthermore, data analysis and outcomes will be defined and registered beforehand, with all data and MRI protocols being shared with the SCI community. The potential benefit to the field of spinal cord injury research and clinical practice is to provide the necessary scientific foundation to determine how MRI can be most effectively used to help translate promising preclinical therapies to human SCI clinical trials. Additionally, these studies will identify imaging biomarkers that provide short-term evidence of the success of an intervention, which will be valuable in the clinical setting as well as in future animal studies to accelerate discovery of treatments. The final goal of the proposed studies is to establish and share with the SCI community a rigorous study design integrated with advanced MRI to promote the translational success of treatments for SCI on their road to success for patients with spinal cord injury.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010413
Entities
People
- Matthew Budde
Organizations
- Medical College of Wisconsin
- United States Army