Validation of qMT and CEST MRI as Biomarkers of Response to Treatment After Lumbar Spinal Cord Injury in Rats

Abstract

The progression and repair of a traumatically injured spinal cord (SCI) involves multifactored processes. Noninvasive, mechanism-informative objective biomarkers could greatly facilitate the translation of findings from preclinical animal models to patient applications. We aimed to develop and validate multiparametric chemical exchange saturation transfer (CEST) and quantitative magnetization transfer (qMT) magnetic resonance imaging (MRI) biomarkers for assessing SCI severity, demyelination, and neuroinflammation, as well as the response to neuroprotective drug treatment riluzole. Changes in CEST and qMT MRI metrics before and after a moderate contusion injury at the L1 level of the lumbar spinal cord were compared between two groups of rats that received either the riluzole or a vehicle treatment over 8 weeks. The specificity of these MRI biomarkers was validated by postmortem immunohistology. The functional relevance of these biomarkers was evaluated by correlation with hindlimb sensorimotor and pain behavior. The pool size ratio (PSR) maps from qMT acquisitions of the SCI region in riluzole-treated rats showed increased white matter macromolecular content compared to the HBC vehicle-treated group, suggesting increased myelin levels and possible remyelination of the injured spinal cord. CEST APT pool (3.5 ppm) amplitude decreased at the region rostral to the injury in riluzole-treated rats compared to the vehicle group, indicating potentially reduced neuroinflammatory activity. MRI metrics correlated temporally with behavioral measures of injury severity and recovery. Histological analysis spatially validated MRI-revealed myelination and neuroinflammation status and confirmed differences between the drug and vehicle treatment groups. Quantitative MRI is well suited for monitoring and quantifying the efficacy of pharmacological treatments in preclinical spinal cord injury models. Multiparametric MRI changes in white matter myelination (qMT PSR) and neuroinflammation (CEST APT) in the injured spinal cord were related to injury severity, behavioral deficits, and recovery progression over time. Both imaging metrics captured enhanced recovery from the neuroprotective drug riluzole, supporting the practical utility of these MRI biomarkers.

Keywords: MRI; chemical exchange saturation transfer (CEST); imaging biomarker; neuroprotective treatment; preclinical imaging; quantitative magnetization transfer (qMT); spinal cord injury.