Multiple sclerosis (MS) is the most common chronic inflammatory demyelinating disease. Magnetic resonance imaging (MRI) has been widely used for the evaluation of MS. A common strategy is to employ T1- or T2-weighted fast spin echo or gradient echo sequences to detect the long T2 components in white matter of the brain. Although these sequences are highly sensitive in revealing macroscopic tissue abnormalities in the brain of patients with MS, they are not specific to the pathologic substrate of the MS lesion and have a limited prognostic role. MS is a disease that relatively specifically affects the myelin a lamellar membranous structure consisting of alternating protein and lipid layers which has an ultrashort T2*, and is not detected with conventional clinical sequences. Furthermore, recent studies have shown that Tysabri promoted regeneration and stabilization of damage done to the myelin sheath based on magnetization transfer (MT) imaging. However, MT is an indirect approach to assess myelin. It would be a major achievement to develop MRI techniques for direct morphological and quantitative imaging of myelin in white matter of the brain, and directly visualizing damage to it, as well as monitoring recovery during therapeutic treatment. We have developed Ultrashort Echo Time (UTE) sequences with minimum nominal TEs of 8 s that are 100-1000 times shorter than conventional TEs of several milliseconds or longer. These sequences make it possible to directly detect signal from myelin using clinical scanners. In this proposal, we will further develop UTE sequences for selective imaging of myelin, investigate contrast mechanisms including single adiabatic inversion recovery (SIR), dual adiabatic inversion recovery (DIR) and phase imaging, and develop quantitative UTE techniques to measure T1, T2*, phase and the proton density (PD) of myelin (Aim 1). We will then compare UTE and clinical sequences for morphological and quantitative evaluation of cadaveric human brains without (n=5) and with MS (n=5), and mice (n=20) using a standard cuprizone mouse model. We will compare and correlate the UTE and clinical measures with histopathology, and demonstrate that UTE can reliably assess dynamic changes in myelin during demyelination and remyelination induced by cuprizone treatment in mice (Aim 2). Finally we will apply the UTE techniques to evaluate MS in a longitudinal study of three groups of patients with relapsing-remitting MS (n=10), primary-progressive MS (n=10) and secondary-progressive MS (n=10) subject to Tysabri treatment (pre-, 6, 12 and 24 months post-treatment). A group of healthy volunteers (n=10) will also be recruited for comparison. We will compare UTE and clinical measures of cross-sectional and longitudinal changes in myelin with neurological assessment of expanded disability status scale (EDSS) (Aim 3). We expect that the UTE techniques will provide more specific and sensitive evaluation of the damage to myelin in MS patients subject to Tysabri treatment. The study is likely to improve the specificity of MRI for the diagnosis of MS, understanding of the natural history of the disease, and treatment monitoring.

Public Health Relevance

The goal of this study is to develop novel UTE techniques for direct morphological imaging and quantitative evaluation of myelin in white matter of the brain, to evaluate their efficiency in characterizing myelin in cadaveric human brain specimens without and with multiple sclerosis, and demyelination/remyelination in mice using a cuprizone mouse model, and to apply them to patients subject to longitudinal Tysabri treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS092650-02
Application #
9095465
Study Section
Biomedical Imaging Technology Study Section (BMIT)
Program Officer
Utz, Ursula
Project Start
2015-07-01
Project End
2020-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Fan, Shu-Juan; Ma, Yajun; Zhu, Yanchun et al. (2018) Yet more evidence that myelin protons can be directly imaged with UTE sequences on a clinical 3T scanner: Bicomponent T2* analysis of native and deuterated ovine brain specimens. Magn Reson Med 80:538-547
Carl, Michael; Ma, Yajun; Du, Jiang (2018) Theoretical analysis and optimization of ultrashort echo time (UTE) imaging contrast with off-resonance saturation. Magn Reson Imaging 50:12-16
Lu, Xing; Ma, Yajun; Chang, Eric Y et al. (2018) Simultaneous quantitative susceptibility mapping (QSM) and R2* for high iron concentration quantification with 3D ultrashort echo time sequences: An echo dependence study. Magn Reson Med 79:2315-2322
Jang, Hyungseok; Lu, Xing; Carl, Michael et al. (2018) True phase quantitative susceptibility mapping using continuous single-point imaging: a feasibility study. Magn Reson Med :
Fan, Shu-Juan; Wong, Jonathan; Cheng, Xin et al. (2018) Feasibility of quantitative ultrashort echo time (UTE)-based methods for MRI of peripheral nerve. NMR Biomed 31:e3948
Nguyen, S; Lu, X; Ma, Y et al. (2018) Musculoskeletal ultrasound for intra-articular bleed detection: a highly sensitive imaging modality compared with conventional magnetic resonance imaging. J Thromb Haemost 16:490-499
Fan, Shu-Juan; Ma, Yajun; Chang, Eric Y et al. (2017) Inversion recovery ultrashort echo time imaging of ultrashort T2 tissue components in ovine brain at 3 T: a sequential D2 O exchange study. NMR Biomed 30:
Soman, Salil; Bregni, Jose A; Bilgic, Berkin et al. (2017) Susceptibility-Based Neuroimaging: Standard Methods, Clinical Applications, and Future Directions. Curr Radiol Rep 5:
Sheth, Vipul R; Fan, Shujuan; He, Qun et al. (2017) Inversion recovery ultrashort echo time magnetic resonance imaging: A method for simultaneous direct detection of myelin and high signal demonstration of iron deposition in the brain - A feasibility study. Magn Reson Imaging 38:87-94
He, Qun; Ma, Yajun; Fan, Shujuan et al. (2017) Direct magnitude and phase imaging of myelin using ultrashort echo time (UTE) pulse sequences: A feasibility study. Magn Reson Imaging 39:194-199

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