The recently discovered glymphatic system performs a similar function in the brain parenchyma as the lymphatic system performs in other organs of the body. It circulates cerebral spinal fluid (CSF) during sleep, clearing harmful chemical and cellular waste products from the brain. The glymphatic system is vital for maintaining normal brain health, while its failure to cleanse brain tissue can exacerbate the neurodegenerative sequelae of Traumatic Brain Injury (TBI). Currently no non-invasive in vivo MRI method exists to characterize the distribution or assess the efficacy of glymphatic transport within brain parenchyma.To address this critical need, we plan to develop a family of novel non-invasive in vivo Dispersion MRI methods to characterize CSF transport (diffusion, advection, and dispersion) within each brain voxel. One method entails separating the diffusion tensor (from DTI) into a purely diffusive and flow-induced mixing or dispersive part. Another method extends mean apparent propagator (MAP) MRI, to enable us to measure molecular diffusion, advection (bulk flow), and dispersive mixing. We also plan to measure correlations between and among molecular displacements both in time and in space as way to assess mixing using the “non-local dispersion tensor” formalism, while another method involves direct measurement of temporal correlations between solvent (CSF) displacements and velocities. Collectively, these approaches will allow us to characterize the efficacy of fluid mixing throughout the brain. To make these assessments, we plan to measure and map salient, intrinsic, dimensionless parameters that characterize the type and efficacy of molecular transport in each voxel in brain parenchyma. Initially, we plan to test and assess all of these MR methods using flow phantoms (packed beds) consisting of cell-sized beads immersed in a moving interstitial solvent. Once tested, vetted and calibrated, we plan to migrate these methods to assess their suitability for use pre-clinically, in the brains of awake and sedated mice.Our working hypothesis is that in regions where molecular transport is diffusion-dominated, molecular clearance via the glymphatic system will be poor, whereas in regions where molecular transport is advection dominated, resulting in dispersive mixing, molecular clearance will be effective. Moreover, stagnant, diffusion-dominated regions may promote the accumulation of harmful protein and cell debris (like sediments settling in a stream bed), potentially leading to further pathology (e.g., Chronic Traumatic Encephalopathy).Specifically, we plan to develop a mathematical/physics framework, NMR and MRI pulse sequences, and a data processing pipeline to analyze, display, measure, and map intrinsic dimensionless parameters that characterize the efficacy of CSF transport and mixing in brain parenchyma. We plan to design, develop, and use porous media-based MRI phantoms and flow cells to vet and validate our experimental framework and theoretical models. Finally, we plan to migrate these various MRI acquisition and analysis pipelines to CNRM’s Translational Imaging Core (USUHS) to scan awake and sedated mice to test for significant, quantitative regional and/or global differences in CSF glymphatic transport among these different groups.There are only published NMR measurements of dispersion processes and none specifically designed for in vivo applications. We plan to combine novel NMR measurements of diffusion, advection, and dispersion with MR imaging to characterize the efficacy of CSF transport and molecular mixing throughout the living brain. We plan to use this conceptual framework to develop a family of novel intrinsic quantitative “stains” which we plan to use as physiological biomarkers to assess the efficacy of regional glymphatic clearance in the brain on a voxel-by-voxel basis.The successful completion of this project would lead to new in vivo methods to follow and assess normal molecular transport via CSF during wakefulness and sleep, and provide a means to detect local glymphatic transport abnormalities (for instance regions of stagnant flow) in the living brain, which could result in disease or degeneration. This new imaging methodology could lead to a) improved monitoring and prognosis in mTBI, b) improved assessment of therapy and rehabilitation strategies, and c) recommendations for personalized strategies to improve glymphatic clearance. As none of our proposed approaches require the injection of contrast agents into CSF compartments, they are much more likely to be tolerated by patients and used in a clinical setting.
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