MS is a chronic inflammatory disease of the CNS with primary destruction of myelin sheaths. It has been known for decades that axonal loss also occurs in MS. In principle, the functional deficit induced by inflammation and demyelination may be reversible. In contrast, the damage to axons and neurons is likely to be irreversible once the threshold of compensation is exceeded. Thus, it has been widely speculated that axonal loss is the pathologic correlate of irreversible neurological impairment in MS. However, axonal loss is not always evident in lesions from patients who are severely affected. The complexity and heterogeneity of the underlying mechanisms of MS require new para-clinical markers for more accurate diagnosis and more precise therapeutic management of the disease. In the proposed studies, a new diffusion tensor imaging (DTI) based method for noninvasive detection of axonal damage in central nervous system (CNS) white matter will be presented and evaluated using animal models of MS. Pre-translational validation will employ human autopsy CNS tissues. The directional diffusivities derived by diffusion tensor imaging describe water movement parallel to (k , axial diffusivity) and perpendicular to (A,i, radial diffusivity) axonal tracts. We have previously proposed and validated that decreasedXy is associated with axonal injury and dysfunction, and increased^ is associated with myelin injury in mouse models of white matter injury. Therefore, a significant reduction inK in CNS white matter in MS patients or in mice with experimental autoimmune encephalomyelitis (EAE) will be suggestive of axonal degeneration and a poor long-term prognosis. To test our hypothesis, EAE will be induced by active immunization in two mouse strains to mimic progressive, non-remitting forms of MS (C57BL/6 mice) and relapsing-remitting MS (RRMS;SJL mice). We predict that axonal damage will be associated with non-remitting neurological defects. This will occur early in C57BL/6 mice reflecting this model's non-remitting nature. In SJL mice, early axonal damage will correlate with incomplete remission following acute peaking of neurological deficits, whereas axonal integrity will be retained with full remissions. In both strains, the extent of axonal damage will closely relate to the duration of the acute peaking of neurological deficits - presumably caused by acute inflammatory responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS054194-05
Application #
7755369
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Utz, Ursula
Project Start
2006-08-15
Project End
2012-01-31
Budget Start
2010-02-01
Budget End
2012-01-31
Support Year
5
Fiscal Year
2010
Total Cost
$365,291
Indirect Cost
Name
Washington University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Cross, Anne H; Song, Sheng-Kwei (2017) ""A new imaging modality to non-invasively assess multiple sclerosis pathology"". J Neuroimmunol 304:81-85
Chang, Sidney T; Xu, Junqian; Trinkaus, Kathryn et al. (2014) Optic nerve diffusion tensor imaging parameters and their correlation with optic disc topography and disease severity in adult glaucoma patients and controls. J Glaucoma 23:513-20
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
Tu, Tsang-Wei; Kim, Joong H; Yin, Feng Qin et al. (2013) The impact of myelination on axon sparing and locomotor function recovery in spinal cord injury assessed using diffusion tensor imaging. NMR Biomed 26:1484-95
Wang, Xiaojie; Brieland, Joan K; Kim, Joong H et al. (2013) Diffusion tensor imaging detects treatment effects of FTY720 in experimental autoimmune encephalomyelitis mice. NMR Biomed 26:1742-50
Wang, Qing; Vlkolinsky, Roman; Xie, Mingqiang et al. (2012) Diffusion tensor imaging detected optic nerve injury correlates with decreased compound action potentials after murine retinal ischemia. Invest Ophthalmol Vis Sci 53:136-42
Özcan, Alpay; Quirk, James D; Wang, Yong et al. (2011) The validation of complete Fourier direct MR method for diffusion MRI via biological and numerical phantoms. Conf Proc IEEE Eng Med Biol Soc 2011:3756-9
Kim, Joong Hee; Wu, Tzy-Haw; Budde, Matthew D et al. (2011) Noninvasive detection of brainstem and spinal cord axonal degeneration in an amyotrophic lateral sclerosis mouse model. NMR Biomed 24:163-9
Klawiter, Eric C; Schmidt, Robert E; Trinkaus, Kathryn et al. (2011) Radial diffusivity predicts demyelination in ex vivo multiple sclerosis spinal cords. Neuroimage 55:1454-60
Wang, Qing; Song, Sheng-Kwei; Zhang, Huiying et al. (2011) Photoreceptor degeneration changes magnetic resonance imaging features in a mouse model of retinitis pigmentosa. Magn Reson Med 65:1793-8

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