Myelin disruption is a characteristic pathological feature of ischemic brain tissue damage. Recent studies suggest that an extent of demyelination and subsequent remyelination after stroke may serve as potential prognostic indicators of either irreversible necrosis or structural repair and functional recovery of brain tissues. Assessment of demyelination and remyelination in stroke patients could provide fundamentally new objective biomarkers for treatment monitoring and predicting rehabilitation outcomes. To date, there have been no histologically validated clinically suitable noninvasive imaging methods that could enable quantitative assessment of demyelination and remyelination dynamics in stroke in a clinical setting. A newly emerged quantitative MRI method enables fast and robust in vivo mapping of the brain myelination based on the physical principle of measuring macromolecular proton fraction (MPF). MPF is a biophysical parameter that describes the amount of macromolecular protons involved into magnetization exchange with free water protons in biological systems. During past decade, MPF has attracted remarkable attention as a quantitative biomarker of myelin due to its high sensitivity to demyelination in normal-appearing white and gray matter and strong correlations between MPF and histologically determined myelin content. A recently developed fast MPF mapping method provides a new approach for MPF measurements, achieves critical improvement in time efficiency, and greatly simplifies image acquisition and processing. While potentially translatable to clinics, this technology is still difficult to use in stroke due the confounding effect of brain edema, which can mask myelin content changes, especially at early stroke stages. The ultimate goals of the proposed project are to develop a modified fast MPF mapping method that will be insensitive to edema and enable its translation into stroke clinics as a diagnostic and prognostic imaging tool. As a key technical solution of the edema sensitivity problem, the project introduces a concept of dilution-corrected MPF (DC-MPF) that can be measured from a combination of magnetization transfer and relaxation data obtained using fast imaging sequences. The project further aims to provide a comprehensive histological and biochemical validation of the new method in the contexts of specificity to myelin content changes and insensitivity to water content changes at different infarct stages using a rat ischemic stroke model. For this purpose, temporal evolution of the ischemic lesion will be monitored over all stages (from acute to late chronic) in a series of rodent experiments, and the results of DC- MPF mapping will be compared with existing imaging techniques, histology, immunohistochemistry, and biochemical brain tissue analysis. All animal imaging experiments will be carried out on a human 3T MRI platform to ensure the applicability of the image acquisition and processing solutions developed in the project to human brain studies. Upon accomplishing the project goals, the fast method for DC-MPF mapping will be fully validated at clinical magnetic field strength and ready for clinical translation.
Recent studies suggest that monitoring of the loss and recovery of myelin in brain tissues after ischemic stroke can be a valuable prognostic indicator of subsequent irreversible tissue damage or repair. A new imaging technique, macromolecular proton fraction (MPF) mapping, enables quantitative estimation of myelin content changes in various pathological conditions including brain ischemia. For future application of this technique in stroke patients, the project is aimed at comprehensive histological and biochemical validation of MPF mapping in an animal model of ischemic stroke using clinical imaging equipment.
