Validating diffusion MRI biomarkers of inflammation and axon pathologies in EAE

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public health. If the application is funded, this description, as is, will become public information. Therefore, do not include proprietary/confidential information. DO NOT EXCEED THE SPACE PROVIDED. We previously demonstrated that diffusion tensor imaging (DTI) successfully detects axon and myelin injury through decreased axial diffusivity (λ║, parallel to the white-matter tract) and increased radial diffusivity (λ, perpendicular to the white-matter tract) in animal models of central nervous system (CNS) diseases and injuries. During the initial Program Project funding period, we identified confounding factors, such as inflammation and tissue loss, causing misinterpretation of DTI-detected axonal pathologies. Thus, we developed a novel diffusion basis spectrum imaging (DBSI) to detect, differentiate, and quantify the extent of inflammation, and axon/myelin injury (Wang et al. 2011). In this PPG renewal, in vivo DBSI will be used to document the evolution of inflammation, axonal injury, and demyelination in optic nerve and spinal cord white-matter tracts in murine EAE, correlating with neurological impairment. DBSI-determined pathologies will be correlated with immunohistochemistry (IHC) during the course of EAE to validate DBSI injury markers. Functional impairment will be correlated with individual and/or combinations of axonal pathologies determined by DBSI and IHC to ascertain which best corresponds to clinical impairments. To explore the use of DBSI as an endpoint for clinical trials, the effect of FTY720 treatment on functional impairment in EAE will be correlated with DBSI-determined axonal pathologies in optic nerve and spinal cord tracts and confirmed by IHC. In addition, we will use both DBSI and the widely-reported manganese enhanced MRI to concomitantly assess the anterograde axonal transport rate of optic nerve in control vs. EAE mice to determine the relationship between axonal transport dysfunction and DBSI-determined axonal pathologies. This would allow an opportunity to delineate whether inflammation or axonal injury of optic nerve underlies functional deficits and to define the role of axonal transport in optic neuritis. If axonal transport defects occur early and persist (as suggested by our preliminary data), this may be a potential therapeutic target.