NIH Reporter #1R21NS153375-01

Tracking Peripheral Nerve Wallerian Degeneration Using Ferrumoxytol and Serum Biomarkers

This NIH grant funds a project at Washington University to develop novel diagnostic methods for peripheral nerve injuries using MR neurography with ferumoxytol and blood biomarkers. The study involves a surgical nerve injury model in below-the-knee amputation patients to track nerve degeneration and improve early diagnosis and treatment.

Description

Diagnostic evaluation of peripheral nerve injuries (PNIs) currently relies on a subjective clinical examination, electrodiagnostic testing (EDX), and imaging. However, EDX, is unreliable acutely (<4 weeks post injury), at a time when it is most critical to understand the severity of a nerve injury. Conventional imaging can detect whether a nerve is ruptured but is not reliable in discerning whether stretch or crush injuries will or will not recover. This limitation is particularly problematic when treating nerve injuries, as surgical intervention should be performed as early as possible to improve the chance of recovery. Radiologists at Hospital for Special Surgery and peripheral nerve surgeons at Washington University in St. Louis will combine a novel contrast agent for MR neurography with novel use of blood biomarkers in an innovative surgical technique to accurately diagnosis peripheral nerve injury. Aim 1: Serum neurofilament light chain (sNfL) and peripherin are protein markers released into the bloodstream after nerve injury will detect the presence of and depict the severity of nerve injury. Aim 2: Detection of Wallerian degeneration that occurs in nerve injury can be identified using MR neurography with ferumoxytol, an ultrasmall, superparamagnetic iron oxide imaging (USPIO) contrast agent that is taken up by macrophages involved in nerve degeneration. Quantitative MRI will also evaluate for acute changes of increased muscle perfusion and muscle edema that ensue with denervation. This project will investigate the relationship of location and timing of nerve injury with these serum and imaging biomarkers using an innovative and reproducible clinical paradigm: a surgical, human nerve injury model comprising a clinically indicated below-the-knee amputation (BKA) that includes a deliberate transection of the common peroneal nerve (CPN), retention of the transected stump and transfer of the proximal nerve into the lateral gastrocnemius motor branch. Longitudinal assessments in n=15 BKA patients, at baseline post-surgery, 6-weeks, and 6-months post-surgery will characterize temporal changes in both serum and imaging biomarkers. This project will develop novel diagnostic algorithms to facilitate early identification of location and degree of peripheral nerve injury. This paves the way for future validation of such an algorithm in larger clinical trials towards a paradigm shift in expeditious care of peripheral nerve injuries and improved patient care outcomes.

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