During the initial funding period, our group developed a novel Diffusion Basis Spectrum Imaging (DBSI) method to simultaneously detect and quantitate inflammation, demyelination and axon injury in vivo using diffusion imaging (Wang et al. 2011). DBSI has substantially improved the accuracy and specificity of our prior diffusion tensor imaging (DTI) approach, by overcoming the main inadequacies of DTI. We hypothesize that DBSI can quantitate the proportions of axon injury, demyelination, and inflammation in CNS of MS patients. We previously showed using a mouse model that DBSI detects and quantitates axonal and myelin injuries that had escaped detection by standard imaging, and by DTI. Our preliminary data now include validation of DBSI using autopsied and biopsied human specimens, with favorable correlations with human histology. We also now have longitudinal data spanning 1.5 yrs, and comparisons of DBSI with magnetization transfer imaging (MTI). In Project 3, we will apply DBSI to humans with MS, comparing it to standard MRI, DTI and MTI. Project 3 will classify MS lesion subtypes by measures of axon injury, demyelination, and inflammation (cellularity and increased free water due to edema or tissue loss), and follow the patients over 4 years to identify predictors and correlates of clinical deterioration. We expect to achieve this using DBSI by differentiating prominent axonal injury vs. axon preservation, and demyelination vs. myelin preservation/ remyelination. We will examine established persistent black holes (PBHs) (new sub-aim), and perform longitudinal assessments of gadolinium-enhancing (Gd+) MS lesions to determine if DBSI will predict PBH formation, representing severe axon loss. With its ability to profile lesions and normal-appearing CNS, DBSI could help non-invasively elucidate the substrate of MS lesion formation and detect inflammation behind an intact blood-CNS-barrier (not detected by Gd+). DBSI has potential to aid development and testing of new therapies for progressive MS where loss of axons and tissue integrity are believed to play a large role.

Public Health Relevance

Multiple Sclerosis affects about 2 million people worldwide, yet we do not even understand what causes it. The pathogenesis of progressive MS, for which no effective disease modifying treatments have yet been developed, is particularly unclear. One reason the field has been slow to fully understand MS is that CNS tissue sampling is rare (due to potential to cause harm), and the disease changes with time. We developed a new imaging method for use in MS to detect and measure loss of myelin and nerve fibers, as well as inflammation. Using a clinical MRI scanner, this is a non-invasive and safe way to see the underlying pathology in brains of people with MS. Upon validation, this method will lead to better understanding of the underlying MS disease process, and should also improve our ability to test new treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
2P01NS059560-06A1
Application #
8741886
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
$331,731
Indirect Cost
$114,084
Name
Washington University
Department
Type
DUNS #
068552207
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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