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Magnetic Resonance Imaging of Myelin Water: Principles and Applications1Radiology, University of British Columbia, Vancouver, BC, Canada, 2Pathology & Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada, 3International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, BC, Canada, 4Medicine, University of British Columbia, Vancouver, BC, Canada, 5Interior Health, Kelowna, BC, Canada, 6Computer Science, Mathematics, Physics & Statistics, University of British Columbia Okanagan, Kelowna, BC, Canada, 7Physics & Astronomy, University of British Columbia, Vancouver, BC, Canada, 8Kinesiology, University of British Columbia, Vancouver, BC, Canada, 9Pediatrics, University of British Columbia, Vancouver, BC, Canada, 10Physical Therapy, University of British Columbia, Vancouver, BC, Canada
Synopsis
Myelin water imaging (MWI) provides quantitative and specific mapping of myelin content in-vivo. Water trapped between myelin bilayers have a short T2 relaxation time; the fractional proportion of this myelin water signal correlates strongly with histological staining for myelin. MWI has successfully been used to study both the brain and spinal cord where it can increase our understanding of development, aging and disease processes, and may also improve accuracy of diagnosis, prognosis and assessment of therapeutic response. Moving forward, MWI is expected to play an important role in the development and monitoring of new treatments targeted at remyelination and neuroprotection.
Purpose
To provide an overview of the principles and applications of myelin water imaging in neurological disorders. The specific objectives are to:
1. Explain the anatomical basis of myelin water.
2. Describe the MRI acquisition and analysis of multi-echo T2-relaxation based myelin water imaging.
3. Summarize key myelin water imaging findings in healthy brain and spinal cord tissue.
4. Review myelin water imaging abnormalities in different central nervous system (CNS) developmental and acquired pathological conditions
5. Learn how myelin water findings compare to other quantitative neuroimaging MR techniques such as diffusion tensor, magnetization transfer imaging and frequency shift imaging.
Outline of Content
1. What is the value of measuring myelin?
2. Background on myelin water imaging technique (a. anatomical basis of myelin water, b. data acquisition, c. data analysis)
3. Is myelin water actually related to myelin? Histological validation in preclinical models and post-mortem human tissue
4. Myelin water in healthy tissue (a. brain, b. spinal cord)
5. Myelin water in pathological or abnormal tissue (a. multiple sclerosis, b. neuromyelitis optica, c. stroke, d. schizophrenia, e. autism, f. primary and amyotrophic lateral sclerosis, g. concussion, h. phenylketonuria, i. neurofibromatosis, j. Niemann-Pick Disease, k. spinal cord injury)
6. Comparison of myelin water to other quantitative neuroimaging methods
7. What is the significance and future of myelin water imaging?
Summary
Accurately measuring myelin in-vivo will improve our understanding of development, aging and neurological diseases as well as enable better assessment of myelin-targeted therapies. Although conventional MRI can detect pathological changes, it lacks specificity for the type(s) of tissue injury and cannot detect abnormalities in the so-called normal appearing white matter. More sophisticated MRI techniques can provide more specific information about myelin content in the CNS. MRI signal in CNS tissue arises almost entirely from water in different physical environments with unique T2 relaxation times1, 2. Water trapped between myelin bilayers (myelin water, Figure 1) has a short T2, while intra/extra-cellular water has a longer T2. The amount of water in each environment can be measured using a multi-echo spin-echo approach, which samples the MRI signal multiple times during T2 relaxation3-9. A fit of the T2 decay curve (signal vs. time) determines the size of the different water environments10. Several other approaches to myelin water measurement and analysis have also been proposed11-22.
Pathology-MRI validation in preclinical models and post-mortem multiple sclerosis CNS tissue (Figure 2) show excellent quantitative agreement between multi-echo derived myelin water content and histological staining for myelin2, 23-30. Myelin water imaging has successfully demonstrated changes with development31-35, regional variation in normal brain (Figure 3)3, 36 and spinal cord37-39, and myelin abnormalities in multiple sclerosis (Figure 4)10, 40-43, neuromyelitis optica44, stroke (Figure 4)45, schizophrenia46, 47, autism48, dyslexia49, dyscalculia50, primary/amyotrophic lateral sclerosis51, concussion52, phenylketonuria53, neurofibromatosis54, Niemann-Pick Disease55, and spinal cord injury (Figure 5)56, in both cross-sectional and longitudinal studies. Several clinical trials have included myelin water as an outcome measure57, 58
Several other quantitative MR methods are also influenced by myelin, including magnetization transfer ratio (MTR), diffusion tensor imaging (DTI), frequency shift imaging (FSI) and magnetic resonance spectroscopy (MRS). However, the lack of strong correlation between MTR, DTI and FSI and myelin water suggest these measures provide complementary information; the correlation between MRS and myelin water is currently being investigated59-61.
In summary, myelin water is a specific imaging biomarker that provides quantitative mapping of myelin content in-vivo. It can increase our understanding of development, aging, disease processes and may improve accuracy of diagnosis, prognosis and assessment of therapeutic response. Moving forward, myelin water imaging is expected to play an important role in the development and monitoring of new treatments targeted at remyelination and neuroprotection.
Acknowledgements
We sincerely thank all participants for studies done locally at our centre, as well as the MRI technologists and administrator. Funding support for work includes Multiple Sclerosis Society of Canada, NSERC, CIHR, Michael Smith Foundation for Health Research, the Cervical Spine Research Society, London Drugs Award for Research Excellence, a Vancouver Hospital and Health Sciences Centre Interdisciplinary Grant, and a seed grant from the International Collaboration on Repair Discoveries.References
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Figures
Figure 4 - Myelin water imaging can monitor pathology in diseases where myelin is damaged such multiple sclerosis (MS) and stroke.
Top: MS lesions show heterogeneous reductions (pink arrows: 2 areas of T1 enhancement, one area has myelin loss while the other does not; yellow arrows: T1 black-holes show different degrees of myelin loss beyond the T1 hypointensity). Normal appearing white matter has 16% less myelin than controls.40
Bottom: Ischemic stroke demonstrates white matter myelin loss compared to controls, including global normal appearing white matter: -13.8%; ipsilesional posterior limb of internal capsule: -14.9%; and contralateral posterior limb of internal capsule: -10.0%.45
