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)
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
Budget End
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
Lin, Tsen-Hsuan; Spees, William M; Chiang, Chia-Wen et al. (2014) Diffusion fMRI detects white-matter dysfunction in mice with acute optic neuritis. Neurobiol Dis 67:1-8
Lin, Tsen-Hsuan; Chiang, Chia-Wen; Trinkaus, Kathryn et al. (2014) Manganese-enhanced MRI (MEMRI) via topical loading of Mn(2+) significantly impairs mouse visual acuity: a comparison with intravitreal injection. NMR Biomed 27:390-8
Wang, Xiaojie; Cusick, Matthew F; Wang, Yong et al. (2014) Diffusion basis spectrum imaging detects and distinguishes coexisting subclinical inflammation, demyelination and axonal injury in experimental autoimmune encephalomyelitis mice. NMR Biomed 27:843-52
Chiang, Chia-Wen; Wang, Yong; Sun, Peng et al. (2014) Quantifying white matter tract diffusion parameters in the presence of increased extra-fiber cellularity and vasogenic edema. Neuroimage 101:310-9
Tu, Tsang-Wei; Budde, Matthew D; Xie, Mingqiang et al. (2014) Phase-aligned multiple spin-echo averaging: a simple way to improve signal-to-noise ratio of in vivo mouse spinal cord diffusion tensor image. Magn Reson Imaging 32:1335-43
Cruz-Orengo, Lillian; Daniels, Brian P; Dorsey, Denise et al. (2014) Enhanced sphingosine-1-phosphate receptor 2 expression underlies female CNS autoimmunity susceptibility. J Clin Invest 124:2571-84
Lin, Tsen-Hsuan; Kim, Joong Hee; Perez-Torres, Carlos et al. (2014) Axonal transport rate decreased at the onset of optic neuritis in EAE mice. Neuroimage 100:244-53
Durrant, Douglas M; Daniels, Brian P; Klein, Robyn S (2014) IL-1R1 signaling regulates CXCL12-mediated T cell localization and fate within the central nervous system during West Nile Virus encephalitis. J Immunol 193:4095-106
Williams, Jessica L; Patel, Jigisha R; Daniels, Brian P et al. (2014) Targeting CXCR7/ACKR3 as a therapeutic strategy to promote remyelination in the adult central nervous system. J Exp Med 211:791-9
Spees, William M; Lin, Tsen-Hsuan; Song, Sheng-Kwei (2013) White-matter diffusion fMRI of mouse optic nerve. Neuroimage 65:209-15

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