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.

Public Health Relevance

We developed a new imaging method (DBSI) to detect and measure the loss of myelin and nerve fibers, as well as inflammation in multiple sclerosis and its animal models. Project 1 will use DBSI to determine the severity of inflammation, and axon/myelin injury in optic nerves of EAE mice at various time points during disease to understand how each pathology component contributes to the disease progression. The successful validation and translation of DBSI to the clinic will provide a noninvasive outcome measure for effectively monitoring disease progression and treatment efficacy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
2P01NS059560-06A1
Application #
8741884
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Washington University
Department
Type
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Lin, Tsen-Hsuan; Chiang, Chia-Wen; Perez-Torres, Carlos J et al. (2017) Diffusion MRI quantifies early axonal loss in the presence of nerve swelling. J Neuroinflammation 14:78
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Salimi, Hamid; Cain, Matthew D; Klein, Robyn S (2016) Encephalitic Arboviruses: Emergence, Clinical Presentation, and Neuropathogenesis. Neurotherapeutics 13:514-34
Kim, Joong Hee; Song, Sheng-Kwei; Haldar, Justin P (2016) Signal-to-noise ratio-enhancing joint reconstruction for improved diffusion imaging of mouse spinal cord white matter injury. Magn Reson Med 75:852-8
Yue, Xuyi; Jin, Hongjun; Liu, Hui et al. (2015) A potent and selective C-11 labeled PET tracer for imaging sphingosine-1-phosphate receptor 2 in the CNS demonstrates sexually dimorphic expression. Org Biomol Chem 13:7928-39
Daniels, Brian P; Klein, Robyn S (2015) Knocking on Closed Doors: Host Interferons Dynamically Regulate Blood-Brain Barrier Function during Viral Infections of the Central Nervous System. PLoS Pathog 11:e1005096
Wang, Yong; Sun, Peng; Wang, Qing et al. (2015) Differentiation and quantification of inflammation, demyelination and axon injury or loss in multiple sclerosis. Brain 138:1223-38

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